|
- <html>
- <head><title></title></head>
- <body>
- <h1></h1>
-
- <p></p>
- <p><strong>The dark side of stress (learned helplessness)</strong> </p>
-
- <hr />
- Acetylcholine is the "neurotransmitter" of cholinergic nerves, including the parasympathetic system.
- Cholinesterase (or acetylcholinesterase) is an enzyme that destroys acetylcholine, limiting the action of the
- cholinergic nerves. Attaching a phosphate group to the cholinesterase enzyme inactivates it, prolonging and
- intensifying the action of cholinergic stimulation.
- <hr />
-
- The autonomic nervous system has traditionally been divided into the sympathetic-adrenergic system, and the
- parasympathetic-cholinergic system, with approximately opposing functions, intensifying energy expenditure and
- limiting energy expenditure, respectively. The hormonal system and the behavioral system interact with these
- systems, and each is capable of disrupting the others. Disruptive factors in the environment have increased in
- recent decades.
- <hr />
-
- Living is development; the choices we make create our individuality. If genetically identical mice grow up in a
- large and varied environment, small differences in their experience will affect cell growth in their brains,
- leading to large differences in their exploratory behavior as they age (Freund, et al., 2013). Geneticists used
- to say that "genes determine our limits," but this experiment shows that an environment can provide both
- limitations and opportunities for expanding the inherited potential. If our environment restricts our choices,
- our becoming human is thwarted, the way rats' potentials weren't discovered when they were kept in the standard
- little laboratory boxes. An opportunity to be complexly involved in a complex environment lets us become more of
- what we are, more humanly differentiated. A series of experiments that started at the University of California
- in 1960 found that rats that lived in larger spaces with various things to explore were better at learning and
- solving problems than rats that were raised in the standard little laboratory cages (Krech, et al., 1960).
- Studying their brains, they found that the enzyme cholinesterase, which destroys the neurotransmitter,
- acetylcholine, was increased. They later found that the offspring of these rats were better learners than their
- parents, and their brains contained more cholinesterase. Their brains were also larger, with a considerable
- thickening of the cortex, which is considered to be the part mainly responsible for complex behavior, learning
- and intelligence. These processes aren't limited to childhood. For example, London taxi drivers who learn all
- the streets in the city develop a larger hippocampus, an area of the brain involved with memory. The 1960s
- research into environmental enrichment coincided with political changes in the US, but it went against the
- dominant scientific ideas of the time. Starting in 1945, the US government had begun a series of projects to
- develop techniques of behavior modification or mind control, using drugs, isolation, deprivation, and torture.
- In the 1950s, psychiatry often used lobotomies (about 80,000, before they were generally discontinued in the
- 1980s) and electroconvulsive "therapy," and university psychologists tortured animals, often as part of
- developing techniques for controlling behavior. The CIA officially phased out their MKultra program in 1967, but
- that was the year that Martin Seligman, at the University of Pennsylvania, popularized the idea of "learned
- helplessness." He found that when an animal was unable to escape from torture, even for a very short time, it
- would often fail to even try to escape the next time it was tortured. Seligman's lectures have been attended by
- psychologists who worked at Guantanamo, and he recently received a no-bid Pentagon grant of $31,000,000, to
- develop a program of "comprehensive soldier fitness," to train marines to avoid learned helplessness. Curt
- Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is
- shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally
- to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once
- (Richter, 1957, 1958). Rats which would normally be able to keep swimming in a tank for two or three days,
- would often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter
- made the important discovery that the hearts of the hopeless rats slowed down before they died, remaining
- relaxed and filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. The
- sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress,
- in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't
- previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been
- thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair.
- Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also
- secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has
- some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys
- acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow
- cells), maybe all cells, can secrete cholinesterase. Because cholinergic nerves have been opposed to the
- sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking
- at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation,
- however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or
- hypoglycemia. Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as
- chemicals that mimic the effects of acetylcholine, such as the organophosphate insecticides, can impair the
- ability to think and learn. This suggested to some people that age-related dementia was the result of the
- deterioration of the cholinergic nerves in the brain. Drugs to increase the stimulating effects of acetylcholine
- in the brain (by inactivating cholinesterase) were promoted as treatment for Alzheimer's disease. Although
- herbal inhibitors were well known, profitable new drugs, starting with Tacrine, were put into use. It was soon
- evident that Tacrine was causing serious liver damage, but wasn't slowing the rate of mental deterioration. As
- the failure of the cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the
- similar memantine) was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was
- proposed a few times for treating dementia, and amantadine, which was also considered anticholinergic, was
- proposed for some mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have
- seemed odd to propose that an anticholinergic drug be used to treat a condition that was being so profitably
- treated with a pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker,"
- to protect the remaining cholinergic nerves, so that both drugs could logically be prescribed simultaneously.
- The added drug seems to have a small beneficial effect, but there has been no suggestion that this could be the
- result of its previously-known anticholinergic effects. Over the years, some people have suspected that
- Alzheimer's disease might be caused partly by a lack of purpose and stimulation in their life, and have found
- that meaningful, interesting activity could improve their mental functioning. Because the idea of a "genetically
- determined hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy
- for all kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the
- association of increasing cholinesterase activity with improving brain function should be of interest. The
- after-effect of poisoning by nerve gas or insecticide has been compared to the dementia of old age. The
- anticholinergic drugs are generally recognized for protecting against those toxins. Traumatic brain injury, even
- with improvement in the short term, often starts a long-term degenerative process, greatly increasing the
- likelihood of dementia at a later age. A cholinergic excitotoxic process is known to be involved in the
- traumatic degeneration of nerves (Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been
- recommended for many years to treat traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al.,
- 1986). In 1976 there was an experiment (Rosellini, et al.) that made an important link between the enrichment
- experiments and the learned helplessness experiments. The control animals in the enrichment experiments were
- singly housed, while the others shared a larger enclosure. In the later experiment, it was found that the rats
- "who were reared in isolation died suddenly when placed in a stressful swimming situation," while the
- group-housed animals were resistant, effective swimmers. Enrichment and deprivation have very clear biological
- meaning, and one is the negation of the other. The increase of cholinesterase, the enzyme that destroys
- acetylcholine, during enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by
- increasing the activity of the cholinergic system, we should expect that a cholinergic drug might substitute for
- inescapable stress, as a cause of learned helplessness, and that an anticholinergic drug could cure learned
- helplessness. Those tests have been done: "Treatment with the anticholinesterase, physostigmine, successfully
- mimicked the effects of inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide
- antagonized the effects of physostigmine, and when administered prior to escape testing antagonized the
- disruptive effects of previously administered inescapable shock." (Anisman, et al., 1981.) This kind of
- experiment would suggest that the anticholinesterase drugs still being used for Alzheimer's disease treatment
- aren't biologically helpful. In an earlier newsletter I discussed the changes of growth hormone, and its
- antagonist somatostatin, in association with dementia: Growth hormone increases, somatostatin decreases. The
- cholinergic nerves are a major factor in shifting those hormones in the direction of dementia, and the
- anticholinergic drugs tend to increase the ratio of somatostatin to growth hormone. Somatostatin and
- cholinesterase have been found to co-exist in single nerve cells (Delfs, et al., 1984). Estrogen, which was
- promoted so intensively as prevention or treatment for Alzheimer's disease, was finally shown to contribute to
- its development. One of the characteristic effects of estrogen is to increase the level of growth hormone in the
- blood. This is just one of many ways that estrogen is associated with cholinergic activation. During pregnancy,
- it's important for the uterus not to contract. Cholinergic stimulation causes it to contract; too much estrogen
- activates that system, and causes miscarriage if it's excessive. An important function of progesterone is to
- keep the uterus relaxed during pregnancy. In the uterus, and in many other systems, progesterone increases the
- activity of cholinesterase, removing the acetylcholine which, under the influence of estrogen, would cause the
- uterus to contract. Progesterone is being used to treat brain injuries, very successfully. It protects against
- inflammation, and in an early study, compared to placebo, lowered mortality by more than half. It's instructive
- to consider its anticholinergic role in the uterus, in relation to its brain protective effects. When the brain
- is poisoned by an organophosphate insecticide, which lowers the activity of cholinesterase, seizures are likely
- to occur, and treatment with progesterone can prevent those seizures, reversing the inhibition of the enzyme
- (and increasing the activity of cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar
- effects of progesterone on cholinesterase occur in menstrually cycling women (Fairbrother, et al., 1989),
- implying that this is a general function of progesterone, not just something to protect pregnancy. Estrogen,
- with similar generality, decreases the activity of cholinesterase. DHEA, like progesterone, increases the
- activity of cholinesterase, and is brain protective (Aly, et al., 2011). Brain trauma consistently leads to
- decreased activity of this enzyme (Östberg, et al., 2011; Donat, et al., 2007), causing the acetylcholine
- produced in the brain to accumulate, with many interesting consequences. In 1997, a group (Pike, et al.) created
- brain injuries in rats to test the idea that a cholinesterase inhibitor would improve their recovery and ability
- to move through a maze. They found instead that it reduced the cognitive ability of both the injured and normal
- rats. An anticholinergic drug, selegeline (deprenyl) that is used to treat Parkinson's disease and, informally,
- as a mood altering antiaging drug, was found by a different group (Zhu, et al., 2000) to improve cognitive
- recovery from brain injuries. One of acetylcholine's important functions, in the brain as elsewhere, is the
- relaxation of blood vessels, and this is done by activating the synthesis of NO, nitric oxide. (Without NO,
- acetylcholine constricts blood vessels; Librizzi, et al., 2000.) The basic control of blood flow in the brain is
- the result of the relaxation of the wall of blood vessels in the presence of carbon dioxide, which is produced
- in proportion to the rate at which oxygen and glucose are being metabolically combined by active cells. In the
- inability of cells to produce CO2 at a normal rate, nitric oxide synthesis in blood vessels can cause them to
- dilate. The mechanism of relaxation by NO is very different, however, involving the inhibition of mitochondrial
- energy production (Barron, et al., 2001). Situations that favor the production and retention of a larger amount
- of carbon dioxide in the tissues are likely to reduce the basic "tone" of the parasympathetic nervous system, as
- there is less need for additional vasodilation. Nitric oxide can diffuse away from the blood vessels, affecting
- the energy metabolism of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from
- nitric oxide (Chen, et al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed
- from the intestine (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide
- themselves. Nitric oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011).
- Nitric oxide activates processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production
- of nitric oxide protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh,
- 2013). Brain trauma causes a large increase in nitric oxide formation, and blocking its synthesis improves
- recovery (Hüttemann, et al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and
- the protective anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997).
- Stress, including fear (Campos, et al., 2013) and isolation (Zlatković & Filipović, 2013) can activate the
- formation of nitric oxide, and various mediators of inflammation also activate it. The nitric oxide in a
- person's exhaled breath can be used to diagnose some diseases, and it probably also reflects the level of their
- emotional well-being. The increase of cholinesterase by enriched living serves to protect tissues against an
- accumulation of acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy
- production, and to activate autolytic or catabolic processes, which are probably involved in the development of
- a thinner cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue
- renewal processes are able to predominate in the enriched animals. Environmental conditions that are favorable
- for respiratory energy production are protective against learned helplessness and neurodegeneration, and other
- biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the
- formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat
- neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010).
- Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990). During the
- development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal
- of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the
- animal to inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been
- created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988). Hypothyroidism and excess
- cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar
- symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by
- increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).
- Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease
- (Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and
- degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners,
- which can be contaminated with organophosphate fumes coming from the engine used to compress it. Possibly the
- most toxic component of our environment is the way the society has been designed, to eliminate meaningful
- choices for most people. In the experiment of Freund, et al., some mice became more exploratory because of the
- choices they made, while others' lives became more routinized and limited. Our culture reinforces routinized
- living. In the absence of opportunities to vary the way you work and live to accord with new knowledge that you
- gain, the nutritional, hormonal and physical factors have special importance. Supplements of thyroid and
- progesterone are proven to be generally protective against the cholinergic threats, but there are many other
- factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits the
- production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et al.,
- 2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et al.,
- 2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without excess
- ultraviolet, should be available every day. The cholinergic system is much more than a part of the nervous
- system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing intake of
- phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009), and from
- choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are intended to
- increase the effects of nitric oxide (asparagine, zildenafil/Viagra, minoxidil/Rogaine) and acetylcholine
- (bethanechol, benzpyrinium, etc.) should be avoided.
-
- <h3>REFERENCES</h3>
-
- Acta Biochim Pol. 2011;58(4):513-20. <strong>Neuroprotective effects of dehydroepiandrosterone (DHEA) in
- rat model of Alzheimer's disease. </strong>Aly HF, Metwally FM, Ahmed HH. Psychopharmacology (Berl).
- 1981;74(1):81-7.<strong> Cholinergic influences on escape deficits produced by uncontrollable
- stress.</strong> Anisman H, Glazier SJ, Sklar LS. Biochim Biophys Acta. 2001 Nov
- 1;1506(3):204-11. <strong>Endothelial- and nitric oxide-dependent effects on oxidative metabolism of intact
- artery.</strong> Barron JT, Gu L, Parrillo JE. Psychiatry Res. 1987 Jul;21(3):267-75.<strong
- > Triiodothyronine potentiation of antidepressant-induced reversal of learned helplessness in
- rats. </strong>Brochet DM, Martin P, Soubrié P, Simon P. Behav Brain Res. 2013 Aug 12. pii:
- S0166-4328(13)00482-8. <strong>Increased nitric oxide-mediated neurotransmission in the medial prefrontal
- cortex is associated with the long lasting anxiogenic-like effect of predator exposure. </strong>Campos
- AC, Piorino EM, Ferreira FR, Guimarães FS. J Biomed Sci. 2001 Nov-Dec;8(6):475-83.<strong> Engagement of
- inducible nitric oxide synthase at the rostral ventrolateral medulla during mevinphos intoxication in the
- rat.</strong> Chang AY, Chan JY, Kao FJ, Huang CM, Chan SH. Science. 1984 Jan
- 6;223(4631):61-3. <strong>Coexistence of acetylcholinesterase and somatostatin-immunoreactivity in neurons
- cultured from rat cerebrum.</strong> Delfs JR, Zhu CH, Dichter MA. Neurosci Bull. 2011
- Dec;27(6):366-82. <strong>Nitric oxide in neurodegeneration: potential benefits of non-steroidal
- anti-inflammatories. </strong>Doherty GH.18. Brain Inj. 2007 Sep;21(10):1031-7. <strong
- >Alterations of acetylcholinesterase activity after traumatic brain injury in rats.</strong> Donat CK,
- Schuhmann MU, Voigt C, Nieber K, Schliebs R, Brust P. Environ Res. 1989 Aug;49(2):181-9.<strong
- > Influence of menstrual cycle on serum cholinesterase.</strong> Fairbrother A, Wagner SL, Welch S,
- Smith BB. Pharmacol Biochem Behav. 1990 Aug;36(4):775-8.<strong> Bright light blocks the capacity of
- inescapable swim stress to supersensitize a central muscarinic mechanism.</strong> Flemmer DD, Dilsaver
- SC, Peck JA. J Biol Chem. 2006 Feb 24;281(8):4779-86. <strong>Hypothyroid phenotype is contributed by
- mitochondrial complex I inactivation due to translocated neuronal nitric-oxide synthase. </strong
- >Franco MC, Antico Arciuch VG, Peralta JG, Galli S, Levisman D, López LM, Romorini L, Poderoso JJ, Carreras MC.
- J Neurotrauma. 2006 Sep;23(9):1343-54. <strong>Neuroprotection by selective inhibition of inducible nitric
- oxide synthase after experimental brain contusion. </strong>Gahm C, Holmin S, Wiklund PN, Brundin L,
- Mathiesen T. Exp Neurol. 2005 Jun;193(2):522-30. <strong>Progesterone suppresses the inflammatory response
- and nitric oxide synthase-2 expression following cerebral ischemia. </strong> Gibson CL,
- Constantin D, Prior MJ, Bath PM, Murphy SP. J Neurosci. 2008 Nov 5;28(45):11500-10. <strong
- >Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin
- inhibition and selective reduction of Thr231-phosphotau.</strong> Green KN, Steffan JS, Martinez-Coria
- H, Sun X, Schreiber SS, Thompson LM, LaFerla FM. Cent Nerv Syst Trauma. 1986 Spring;3(2):163-73.<strong
- > Metabolic and neurophysiologic sequelae of brain injury: a cholinergic hypothesis. </strong>Hayes
- RL, Stonnington HH, Lyeth BG, Dixon CE, Yamamoto T. Physiol Behav. 2006 Jan 30;87(1):114-9. <strong
- >Peripheral triiodothyronine (T(3)) levels during escapable and inescapable footshock.</strong> Helmreich
- DL, Crouch M, Dorr NP, Parfitt DB.
-
- <strong>Neuroscience. 2008 Jun 26;154(3):861-8. Nicotinamide treatment induces behavioral recovery when
- administered up to 4 hours following cortical contusion injury in the rat.</strong> Hoane MR, Pierce
- JL, Holland MA, Anderson GD. Neuroscience. 2008 Jan 2;151(1):148-54. <strong>Suppression of the inducible
- form of nitric oxide synthase prior to traumatic brain injury improves cytochrome c oxidase activity and
- normalizes cellular energy levels. </strong>Hüttemann M, Lee I, Kreipke CW, Petrov T. Neuroreport. 2000
- Apr 27;11(6):1173-6. <strong>Tacrine, a reversible acetylcholinesterase inhibitor, induces
- myopathy. </strong>Jeyarasasingam G, Yeluashvili M, Quik M. J Pharmacol Exp Ther. 2000
- Oct;295(1):314-20.<strong> Nitric oxide is involved in acetylcholinesterase inhibitor-induced myopathy in
- rats. </strong>Jeyarasasingam G, Yeluashvili M, Quik M. Naunyn Schmiedebergs Arch Pharmacol. 2010
- Oct;382(4):311-20. <strong>Effect of phosphamidon on convulsive behavior and biochemical parameters:
- modulation by progesterone and 4'-chlorodiazepam in rats. </strong>Joshi V, Arora T, Mehta AK, Sharma
- AK, Rathor N, Mehta KD, Mahajan P, Mediratta PK, Banerjee BD, Sharma KK. Environ Toxicol Pharmacol. 1997 Feb
- 15;3(1):53-6. <strong>A role of nitric oxide in organophosphate-induced convulsions. </strong>Kim YB,
- Hur GH, Lee YS, Han BG, Shin S. J Comp Physiol Psychol. 1960 Dec;53:509-19.<strong> Effects of
- environmental complexity and training on brain chemistry.</strong> Krech D, Rosenzweig MR, Bennett EL.
- Physiol Behav. 1990 Jul;48(1):165-7.<strong> Thyroparathyroidectomy produces a progressive escape deficit
- in rats.</strong> Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT. Neuroscience.
- 2000;101(2):283-7. <strong>Nitric oxide synthase inhibitors unmask acetylcholine-mediated constriction of
- cerebral vessels in the in vitro isolated guinea-pig brain.</strong> Librizzi L, Folco G, de Curtis M.
- J Neurotrauma. 1992 May;9 Suppl 2:S463-74. <strong>Cholinergic and opioid mediation of traumatic brain
- injury.</strong> Lyeth BG, Hayes RL. Neurosci Behav Physiol. 2010 Sep;40(7):737-43. <strong
- >Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation
- to hypoxia.</strong> Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG,
- Khomenko IP, Mashina SY, Pokidyshev DA, Malyshev IY. Eur J Pharmacol. 1987 Feb 24;134(3):345-8.<strong
- > Triiodothyroacetic acid-induced reversal of learned helplessness in rats. </strong>Massol J, Martin
- P, Soubrié P, Simon P. Eur J Pharmacol. 1988 Aug 2;152(3):347-51. <strong>Triiodothyroacetic acid (TRIAC)
- potentiation of antidepressant-induced reversal of learned helplessness in rats. </strong>Massol J,
- Martin P, Soubrié P, Puech AJ. J Neurosci. 2013 Jul 31;33(31):12557-12568. <strong>Nitric Oxide Mediates
- Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide
- Isomerase.</strong>Obukuro K, Nobunaga M, Takigawa M, Morioka H, Hisatsune A, Isohama Y, Shimokawa H,
- Tsutsui M, Katsuki H. Neurology. 2011 Mar 22;76(12):1046-50. <strong>Cholinergic dysfunction after
- traumatic brain injury: preliminary findings from a PET study.</strong> Östberg A, Virta J, Rinne JO,
- Oikonen V, Luoto P, Någren K, Arponen E, Tenovuo O. 1. Eur J Neurosci. 2013 Jan;37(2):181-9. <strong
- >Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via
- N-methyl-D-aspartate receptor activation.</strong> Petrov KA, Malomouzh AI, Kovyazina IV, Krejci E,
- Nikitashina AD, Proskurina SE, Zobov VV, Nikolsky EE. Brain Res. 2005 Jul 5;1049(1):112-9. <strong
- >Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury.</strong
- > Pettus EH, Wright DW, Stein DG, Hoffman SW. J Neurotrauma. 1997 Dec;14(12):897-905.<strong> Effect
- of tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental
- brain injury. </strong>Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG. Psychosom Med. 1957
- May-Jun;19(3):191-8. <strong>On the phenomenon of sudden death in animals and man.</strong> Richter
- CP. Psychosom Med. 1976 Jan-Feb;38(1):55-8.<strong> Sudden death in the laboratory rat. </strong
- >Rosellini RA, Binik YM, Seligman MP. J Neurosurg. 1954 Jan;11(1):77-83.<strong> The use of cholinergic
- blocking agents in the treatment of cranio-cerebral injuries. </strong>RUGE D. J Neurosurg. 1950
- Sep;7(5):398-402.<strong> Atropine in the treatment of closed head injury.</strong>
- WARD A Jr. Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. <strong>Arsenic toxicity induced
- endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible
- nitric oxide synthase inhibitors.</strong> Sharma B, Sharma PM. Pharmacol Biochem Behav. 2013
- Feb;103(4):821-30. <strong> Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and
- nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of
- hypertension induced vascular dementia in rats. </strong>Sharma B, Singh N. J Neurol Neurosurg
- Psychiatry. 1973 Aug;36(4):581-4.<strong> Creutzfeldt-Jakob disease treated with amantidine. A report of
- two cases. </strong>Sanders WL, Dunn TL. Neuroscientist. 2010 Aug;16(4):435-52. <strong>Nitric
- oxide signaling in brain function, dysfunction, and dementia.</strong> Steinert JR, Chernova T,
- Forsythe ID. FASEB J. 2001 Jun;15(8):1407-9.<strong> Amyloid beta-peptide induces nitric oxide production
- in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide
- synthase inhibitors. </strong>Tran MH, Yamada K, Olariu A, Mizuno M, Ren XH, Nabeshima T. Genes Nutr.
- 2009 December; 4(4): 309–314.<strong> Dietary polyunsaturated fatty acids improve cholinergic transmission
- in the aged brain</strong> Willis LM, Shukitt-Hale B, Joseph JA. Toxicology. 2013 May
- 10;307:3-11. <strong>Linking pesticide exposure and dementia: what is the evidence?</strong> Zaganas
- I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF, Tsatsakis AM. Exp Neurol. 2000
- Nov;166(1):136-52. <strong>Postinjury administration of L-deprenyl improves cognitive function and enhances
- neuroplasticity after traumatic brain injury.</strong> Zhu J, Hamm RJ, Reeves TM, Povlishock JT,
- Phillips LL. Neurochem Int. 2013 Sep;63(3):172-9. <strong>Chronic social isolation induces NF-κB activation
- and upregulation of iNOS protein expression in rat prefrontal cortex.</strong> Zlatković J, Filipović
- D. J Biol Chem. 2006 Feb 24;281(8):4779-86. <strong>Hypothyroid phenotype is contributed by mitochondrial
- complex I inactivation due to translocated neuronal nitric-oxide synthase. </strong>Franco MC, Antico
- Arciuch VG, Peralta JG, Galli S, Levisman D, López LM, Romorini L, Poderoso JJ, Carreras MC. Laboratory of
- Oxygen Metabolism, University Hospital, Facultad de Medicina, University of Buenos Aires, 1120-Buenos Aires,
- Argentina. Although transcriptional effects of thyroid hormones have substantial influence on oxidative
- metabolism,<span><strong> how thyroid sets basal metabolic rate remains obscure.</strong></span>
- <span><strong>Compartmental localization of nitric-oxide synthases is important for nitric</strong></span>
- <span><strong>oxide signaling. We therefore examined liver neuronal nitric-oxide synthase-alpha</strong></span>
- <span><strong>(nNOS) subcellular distribution as a putative mechanism for thyroid effects on</strong></span>
- <span><strong>rat metabolic rate. At low 3,3',5-triiodo-L-thyronine levels, nNOS mRNA increased</strong></span>
- <span><strong>by 3-fold, protein</strong></span> expression by one-fold, and nNOS was selectively
- translocated to mitochondria without changes in other isoforms. In contrast, under thyroid hormone
- administration, mRNA level did not change and nNOS remained predominantly localized in cytosol. In
- hypothyroidism, nNOS translocation resulted in enhanced mitochondrial nitric-oxide synthase activity with
- low O2 uptake. In this context, NO utilization increased active O2 species and peroxynitrite yields and
- tyrosine nitration of complex I proteins that reduced complex activity. Hypothyroidism was also associated
- to high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase
- 1/2 and cyclin D1 levels.
- <span><strong>Similarly to thyroid hormones, but without changing thyroid status, nitric-oxide </strong
- ></span>
- <span><strong>synthase inhibitor N(omega)-nitro-L-arginine methyl ester increased basal</strong></span>
- <span><strong>metabolic rate, prevented mitochondrial nitration and complex I derangement, and </strong
- ></span>
- <span><strong>turned mitogen-activated protein kinase signaling and cyclin D1 expression back</strong></span>
- <span><strong>to control pattern. We surmise that nNOS spatial confinement in mitochondria is a</strong></span>
- <span><strong>significant downstream effector of thyroid hormone and hypothyroid phenotype.</strong></span>
-
- Toxicology. 2013 May 10;307:3-11.<strong> Linking pesticide exposure and dementia: what is the
- evidence? </strong>Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,
- Tsatsakis AM. J Pharmacol Exp Ther. 2000 Oct;295(1):314-20.<strong> Nitric oxide is involved in
- acetylcholinesterase inhibitor-induced myopathy in rats. </strong>Jeyarasasingam G, Yeluashvili M, Quik
- M. Neuroreport. 2000 Apr 27;11(6):1173-6.<strong> Tacrine, a reversible acetylcholinesterase inhibitor,
- induces myopathy.</strong> Jeyarasasingam G, Yeluashvili M, Quik M. Biochem Biophys Res Commun. 2002
- Jan 11;290(1):97-104. NO synthesis, unlike respiration, influences intracellular oxygen tension. Coste J, Vial
- JC, Faury G, Deronzier A, Usson Y, Robert-Nicoud M, Verdetti J. We have developed a new phosphorescent probe,
- PdTCPPNa(4), whose luminescence properties are affected by local variations of intracellular oxygen tension
- (PO(2)). Spectrofluorometric measurements on living human umbilical venous endothelial cells loaded with this
- molecule show that a decrease in extracellular oxygen tension induces a decrease of PO(2), illustrating the
- phenomenon of oxygen diffusion and validating the use of this probe in living cells. Moreover, KCN- or
- 2,4-dinitrophenol-induced modifications of respiration do not lead to detectable PO(2) variations, probably
- because O(2) diffusion is sufficient to allow oxygen supply. On the contrary,<strong> activation by
- acetylcholine or endothelial nitric oxide synthase (eNOS), which produces NO while consuming oxygen, induces
- a significant decrease in PO(2), whose amplitude is dependent on the acetylcholine dose, i.e., the eNOS
- activity level. </strong>Hence, activated cytosolic enzymes could consume high levels of oxygen which
- cannot be supplied by diffusion, leading to PO(2) decrease. Other cell physiology mechanisms leading to PO(2)
- variations can now be studied in living cells with this probe. Science. 1984 Jan 6;223(4631):61-3. <strong
- >Coexistence of acetylcholinesterase and somatostatin-immunoreactivity in neurons cultured from rat
- cerebrum.</strong> Delfs JR, Zhu CH, Dichter MA. Genes Nutr. 2009 December; 4(4): 309–314.<strong
- > Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain</strong
- > Willis LM, Shukitt-Hale B, Joseph JA. Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and
- dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,
- Tsatsakis AM. s sufficient for oxidative phosphorylation (references in ref. 1). These findings indicate that,
- in execution of these tasks, the involved brain tissue switches to aerobic glycolysis. Acta Neurochir Suppl.
- 1997;70:130-3. Topical application of insulin like growth factor-1 reduces edema and upregulation of neuronal
- nitric oxide synthase following trauma to the rat spinal cord. Sharma HS, Nyberg F, Gordh T, Alm P, Westman J.
- Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. <strong>Arsenic toxicity induced
- endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible
- nitric oxide synthase inhibitors.</strong> Sharma B, Sharma PM. 2. Pharmacol Biochem Behav. 2013
- Feb;103(4):821-30. <strong> Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and
- nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of
- hypertension induced vascular dementia in rats. </strong>Sharma B, Singh N. CNS and CVS Research Lab.,
- Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi
- University, Patiala 147002, Punjab, India. <a href="mailto:bhupeshresearch@gmail.com" target="_blank"
- >bhupeshresearch@gmail.com</a>
- Cognitive disorders are likely to increase over the coming years (5-10). Vascular dementia (VaD) has
- heterogeneous pathology and is a challenge for clinicians. Current Alzheimer's disease drugs have had limited
- clinical efficacy in treating VaD and none have been approved by major regulatory authorities specifically
- for this disease. Role of iNOS and NADPH-oxidase has been reported in various pathological conditions but
- there role in hypertension (Hypt) induced VaD is still unclear. This research work investigates the salutiferous
- effect of aminoguanidine (AG), an iNOS inhibitor and 4'-hydroxy-3'-methoxyacetophenone (HMAP), a NADPH oxidase
- inhibitor in Hypt induced VaD in rats. Deoxycorticosterone acetate-salt (DOCA-S) hypertension has been used for
- development of VaD in rats. Morris water-maze was used for testing learning and memory. Vascular system
- assessment was done by testing endothelial function. Mean arterial blood pressure (MABP), oxidative stress
- [aortic superoxide anion, serum and brain thiobarbituric acid reactive species (TBARS) and brain
- glutathione (GSH)], nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl
- cholinesterase activity-AChE) were also measured. DOCA-S treated rats have shown increased MABP with impairment
- of endothelial function, learning and memory, reduction in serum nitrite/nitrate & brain GSH levels
- along with increase in serum & brain TBARS, and brain AChE activity. AG as well as HMAP significantly
- convalesce Hypt induced impairment of learning, memory, endothelial function, and alterations in various
- biochemical parameters. It may be concluded that AG, an iNOS inhibitor and HMAP, a NADPH-oxidase inhibitor
- may be considered as potential agents for the management of Hypt induced VaD. Copyright © 2012 Elsevier
- Inc. All rights reserved. [Curr Pharm Des. 2010;16(25):2837-50. Nitric oxide: target for therapeutic strategies
- in Alzheimer's disease. Fernandez AP, Pozo-Rodrigalvarez A, Serrano J, Martinez-Murillo R. "<strong>data
- implicating nitric oxide (NO) in the progression of the disease. The three isoforms of the NO-synthesizing
- enzyme (NOS) operate as central mediators of amyloid beta-peptide (Aβ) action, giving rise to elevated
- levels of NO that contributes to the maintenance, self-perpetuation and progression of the disease.</strong
- > "] J Neuropathol Exp Neurol. 2007 Apr;66(4):272-83. Nitric oxide synthase 3-mediated neurodegeneration
- after intracerebral gene delivery. de la Monte SM, Jhaveri A, Maron BA, Wands JR. "<strong>increased nitric
- oxide synthase 3 (NOS3) expression correlates with apoptosis in cortical neurons and colocalizes with
- amyloid precursor protein (APP)-amyloid beta (Abeta) deposits in the brain."</strong>
-
- Neuroscience. 2000;101(2):283-7. <strong>Nitric oxide synthase inhibitors unmask acetylcholine-mediated
- constriction of cerebral vessels in the in vitro isolated guinea-pig brain.</strong> Librizzi L, Folco
- G, de Curtis M. Pharmacology. 2000 Feb;60(2):82-9. Choline is a full agonist in inducing activation of neuronal
- nitric oxide synthase via the muscarinic M1 receptor. Carriere JL, El-Fakahany EE. Glia. 2003 Jan
- 15;41(2):207-11. Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine
- receptor immunoreactivity in astrocytes. Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R,
- Perry E. 16. Neuroscientist. 2010 Aug;16(4):435-52.
- <strong>Nitric oxide signaling in brain function, dysfunction, and dementia.</strong>
- Steinert JR, Chernova T, Forsythe ID. Neurotoxicity at the Synaptic Interface, MRC Toxicology Unit, University
- of Leicester, Leicester, UK. Nitric oxide (NO) is an important signaling molecule that is widely used in the
- nervous system. With recognition of its roles in synaptic plasticity (long-term potentiation, LTP; long-term
- depression, LTD) and elucidation of calcium-dependent, NMDAR-mediated activation of neuronal nitric oxide
- synthase (nNOS), numerous molecular and pharmacological tools have been used to explore the physiology and
- pathological consequences for nitrergic signaling. In this review, the authors summarize the current
- understanding of this subtle signaling pathway, discuss the evidence for nitrergic modulation of ion
- channels and homeostatic modulation of intrinsic excitability, and speculate about the pathological consequences
- of spillover between different nitrergic compartments in contributing to aberrant signaling in neurodegenerative
- disorders. Accumulating evidence points to various ion channels and particularly voltage-gated potassium
- channels as signaling targets, whereby NO mediates activity-dependent control of intrinsic neuronal
- excitability; such changes could underlie broader mechanisms of synaptic plasticity across neuronal networks. In
- addition, <strong>the inability to constrain NO diffusion suggests that spillover from</strong>
- <strong>endothelium (eNOS) and/or immune compartments (iNOS) into the nervous system</strong>
- <strong>provides potential pathological sources of NO and where control failure in these </strong>
- <strong>other systems could have broader neurological implications. </strong>Abnormal NO signaling could
- therefore contribute to a variety of neurodegenerative pathologies such as stroke/excitotoxicity,
- Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Neurosci Bull. 2011 Dec;27(6):366-82. Nitric
- oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories. Doherty GH.18.
- Neuroscience. 2010 Dec 15;171(3):859-68. Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced
- oxidative and inflammatory responses in astrocytes. Yang X, Askarova S, Sheng W, Chen JK, Sun AY, Sun GY, Yao G,
- Lee JC. Neurosci Behav Physiol. 2010 Sep;40(7):737-43. <strong>Prevention of neurodegenerative damage to
- the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia.</strong> Manukhina EB,
- Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA,
- Malyshev IY. Physiol Behav. 1990 Jul;48(1):165-7.
- <strong>Thyroparathyroidectomy produces a progressive escape deficit in rats.</strong>
- Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT. Department of Anatomy, University of
- Pennsylvania, Philadelphia. Abnormal thyroid status and affective disorders have been associated in the human
- clinical literature. It has recently been shown <strong>that pretreatment with thyroid</strong>
- <strong>hormone can prevent escape deficits produced by inescapable shock in an animal</strong>
- <strong>analogue of depression.</strong> In this report we provide evidence that <strong
- >hypothyroid</strong>
- <strong>status can produce an escape deficit in rats.</strong> While sham-operated rats improved their
- performance on a simple escape task over three days of testing, thyroparathyroidectomized rats showed a
- pronounced decrease in their responses. Markov transition analysis was used to obtain conditional probabilities
- of escaping given a prior escape or failure to escape for the two groups. This analysis shows that the structure
- of the data set may be similar for the two groups. These results suggest that if intact rats learn to escape,
- then hypothyroid rats may learn not to escape. 1. Pharmacol Biochem Behav. 1990 Aug;36(4):775-8.
- <strong>Bright light blocks the capacity of inescapable swim stress to supersensitize a</strong>
- <strong>central muscarinic mechanism.</strong>
- Flemmer DD, Dilsaver SC, Peck JA. Department of Psychiatry, Ohio State University. Clinical and basic
- researchers have proposed that muscarinic cholinergic mechanisms mediate some effects of chronic stress. Chronic
- inescapable (forced) swim stress depletes brain biogenic amines and is used to produce learned helplessness in
- rats. Behavioral and biochemical characteristics of animals in the state of learned helplessness lead some
- investigators to believe this condition provides a useful animal model of depression. <strong>Inescapable
- swim stress</strong>
- <strong>also produces supersensitivity to the hypothermic effect of the muscarinic</strong>
- <strong>agonist oxotremorine in the rat. </strong>The authors previously demonstrated that bright
- light potently induces subsensitivity of a central muscarinic mechanism involved in the regulation of core
- temperature under a variety of circumstances. They now report using a repeated measures design that
- inescapable swim stress of five days duration produces supersensitivity to oxotremorine (increase in thermic
- response of 405%). This <strong>supersensitivity is reversed within five days by treatment
- with</strong>
- <strong>bright light, despite continuation of daily swim stress. Daily inescapable swim</strong>
- <strong>stress was continued beyond cessation of treatment with bright light. </strong>Five days later,
- supersensitivity to the hypothermic effect of oxotremorine was once again evident. Pharmacol Biochem
- Behav. 1986 Aug;25(2):415-21. Neurochemical and behavioral consequences of mild, uncontrollable shock:
- effects of PCPA. Edwards E, Johnson J, Anderson D, Turano P, Henn FA. The present experiments
- examined the role of the serotonergic system in the behavioral deficit produced by uncontrollable shock.
- In Experiment 1: Establishment of model, the behavioral potential of the Sprague-Dawley rat was
- defined. When exposed to mild uncontrollable stress such as a 0.8 mA electric footshock, a significant
- percentage of rats developed a shock escape deficit which was evident when subsequently placed in a shock
- escape paradigm. Serotonin depletion was produced by chronic treatment with p-chlorophenylalanine.
- Biogenic amine levels and 5-HT levels were monitored in various brain areas using HPLC. Following
- chronic treatment with PCPA, the shock escape capability of the Sprague-Dawley rat was
- assessed. <strong>The severe depletion of 5-HT in various brain </strong>
- <strong>regions was highly correlated with a dramatic improvement in the shock escape </strong>
- <strong>scores. Thus, the detrimental effects of exposure to a mild course of inescapable </strong>
- <strong>shock can be prevented by chronic treatment with PCPA</strong>. These experiments implicate the
- serotonergic system as a possible mediator of the "learned helplessness" phenomenon. Biol
- Psychiatry. 1985 Sep;20(9):1023-5. Triiodothyronine-induced reversal of learned helplessness in
- rats. Martin P, Brochet D, Soubrie P, Simon P. Pharmacol Biochem Behav. 1982 Nov;17(5):877-83.
- Evidence for a serotonergic mechanism of the learned helplessness phenomenon. Brown L, Rosellini RA,
- Samuels OB, Riley EP. The present experiments examined the role of the serotonergic system in the
- learned helplessness phenomenon. In Experiment 1, a 200 mg/kg dose of 1-tryptophan injected 30 min prior
- to testing disrupted acquisition of Fixed Ratio 2 shuttle escape behavior. In Experiment 2, a 100 mg/kg
- dose of 5-HTP produced interference with the acquisition of the escape response. Furthermore, this
- interference was prevented by treatment with the serotonergic antagonist methysergide. In Experiment 3,
- animals were pretreated with a subeffective dose of 1-tryptophan in combination with subeffective exposure
- to inescapable shock. These animals showed a deficit in the acquisition of FR-2 shuttle escape. In
- Experiment 4, combined exposure to a subeffective dose of 5-HTP and inescapable shock (40 trials) resulted
- in an acquisition deficit. This deficit was reversed by methysergide. Experiment 5 showed that the
- detrimental effects of exposure to prolonged (80 trials) of inescapable shock can be prevented by
- treatment with methysergide. These studies implicate the serotonergic system as a possible mediator
- of the learned helplessness phenomenon. 45. Med Hypotheses. 2004;63(2):308-21. Brain cholinesterases: II.
- The molecular and cellular basis of Alzheimer's disease. Shen ZX. 2436 Rhode Island Avenue #3, Golden valley, MN
- 55427-5011, USA.
- <a href="mailto:zhengxshen@yahoo.com" target="_blank">zhengxshen@yahoo.com</a>
- Currently available evidence demonstrates that cholinesterases (ChEs), owing to their powerful enzymatic and
- non-catalytic actions, unusually strong electrostatics, and <strong>exceptionally ubiquitous presence and
- redundancy in their</strong>
- <strong>capacity as the connector, the organizer and the safeguard of the brain, </strong>play fundamental
- role(s) in the well-being of cells, tissues, animal and human lives, while they present themselves
- adequately in quality and quantity. The widespread intracellular and extracellular membrane networks of
- ChEs in the brain are also subject to various insults, such as aging, gene anomalies, environmental hazards,
- head trauma, excessive oxidative stress, imbalances and/or deficits of organic constituents. The loss and the
- alteration of ChEs on the outer surface membranous network may initiate the formation of extracellular senile
- plaques and induce an outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the
- intracellular compartments membranous network may give rise to the development of intracellular neurofibrillary
- tangles and induce an inside-out cascade of AD. The abnormal patterns of glycosylation and configuration changes
- in ChEs may be reflecting their impaired metabolism at the molecular and cellular level and causing the
- enzymatic and pharmacodynamical modifications and neurotoxicity detected in brain tissue and/or CSF of patients
- with AD and in specimens in laboratory experiments. The inflammatory reactions mainly arising from
- ChEs-containing neuroglial cells may facilitate the pathophysiologic process of AD. It is proposed that brain
- ChEs may serve as a central point rallying various hypotheses regarding the etio-pathogenesis of AD. 3.
- Neurology. 2011 Mar 22;76(12):1046-50. doi: 10.1212/WNL.0b013e318211c1c4. Cholinergic dysfunction after
- traumatic brain injury: preliminary findings from a PET study. Östberg A, Virta J, Rinne JO, Oikonen V, Luoto P,
- Någren K, Arponen E, Tenovuo O. Department of Neurology, University of Turku and Turku University Central
- Hospital, Turku, Finland. OBJECTIVE: There is evidence that the cholinergic system is frequently involved in the
- cognitive consequences of traumatic brain injury (TBI). We studied whether the brain cholinergic function is
- altered after TBI in vivo using PET. METHODS: Cholinergic function was assessed with
- [methyl-(11)C]N-methylpiperidyl-4-acetate, which reflects the acetylcholinesterase (AChE) activity, in 17
- subjects more than 1 year after a TBI and in 12 healthy controls. All subjects had been without any centrally
- acting drugs for at least 4 weeks. RESULTS: The AChE activity was significantly lower in subjects with TBI
- compared
- <hr />
- 0.004). CONCLUSIONS: Patients with chronic cognitive symptoms after TBI show widely lowered AChE activity across
- the neocortex. © 2011 by AAN Enterprises, Inc. 9. Brain Inj. 2007 Sep;21(10):1031-7. Alterations of
- acetylcholinesterase activity after traumatic brain injury in rats. Donat CK, Schuhmann MU, Voigt C, Nieber K,
- Schliebs R, Brust P. Institute of Interdisciplinary Isotope Research, Permoserstasse 15, 04318 Leipzig,
- Germany. <a href="mailto:donat@iif-leipzig.de" target="_blank">donat@iif-leipzig.de</a>
- OBJECTIVE: The cholinergic system is highly vulnerable to traumatic brain injury (TBI). However, limited
- information is available to what extent the degrading enzyme acetylcholinesterase (AChE) is involved. The
- present study addresses this question. METHOD: Thirty-six anaesthetized Sprague-Dawley rats were subjected
- to sham operation or to TBI using controlled cortical impact (CCI). The AChE activity was histochemically
- determined in frozen brain slices at 2, 24 and 72 hours after TBI. RESULTS: High enzyme activity was observed in
- regions rich in cholinergic innervation such as the olfactory tubercle, basal forebrain, putamen and superior
- colliculi.<strong> Low activity was found in the cortex, cerebellum and particularly in</strong>
- <strong>the white matter. A decrease of AchE activity (20-35%) was found in the</strong>
- <strong>hippocampus and hypothalamus already at 2 hours after TBI. </strong>An increase of approximately
- 30% was found in the basal forebrain at 2 and 24 hours. No changes occurred at 72 hours. CONCLUSION: The
- findings are consistent with impairment of the cholinergic neurotransmission after TBI and suggest the
- involvement of the AChE in short-term regulatory mechanisms. 35. Res Commun Chem Pathol Pharmacol. 1990
- Jun;68(3):391-4. Increase of muscarinic receptor following kainic acid lesions of the nucleus basalis
- magnocellularis in rat brain: an autoradiographic study. Katayama S, Kito S, Yamamura Y. Third Department of
- Internal Medicine, Hiroshima University School of Medicine, Japan. We observed changes in cholinergic markers in
- rat brain seven days after lesioning the nucleus basalis magnocellularis (nbm) with kainic acid. In
- histochemical preparations stained for acetylcholinesterase (AChE), <strong>there was a</strong>
- <strong>marked loss of large AChE reactive neurons within and beneath the nbm on the</strong>
- <strong>injected side, and the AChE positive fibers were greatly decreased particularly</strong>
- <strong>in the IV-VI layers of the frontal and parietal cortices ipsilateral to the</strong>
- kainate lesion. Using in vitro receptor autoradiography, we found a significant increase (about 25%) in 3H-QNB
- binding sites in the I-IV layers of the ipsilateral frontal and parietal cortices (p 0.05, Student's
- t-test). <strong>The area</strong>
- <strong>with decreased AChE activity </strong>and increased density in 3H-QNB binding sites corresponded to
- the innervation of the cholinergic system arising from the nbm. The increase of density in 3H-QNB binding sites
- was considered to reflect the postsynaptic denervation supersensitivity. 36. Hum Exp Toxicol. 1992
- Nov;11(6):517-23. Long-term study of brain lesions following soman, in comparison to DFP and metrazol poisoning.
- Kadar T, Cohen G, Sahar R, Alkalai D, Shapira S. Department of Pharmacology, Israel Institute for Biological
- Research, Ness-Ziona, Israel. The long-term histopathological effects of acute lethal (95 micrograms kg-1)
- and sublethal (56 micrograms kg-1) doses of soman were studied in rats and were compared to lesions caused
- by equipotent doses of either another cholinesterase (ChE) inhibitor, DFP (1.8 mg kg-1), or a
- non-organophosphorus convulsant, metrazol (100 mg kg-1). Severe toxic signs were noted following one LD50 dose
- administration of all the compounds, yet only soman induced brain lesions. Moreover, even when administered at a
- sublethal dose (0.5 LD50), soman induced some histological changes without any clinical signs of intoxication.
- Soman-induced brain lesions were assessed quantitatively using a computerized image analyser. The analysis was
- carried out for up to 3 months following administration, and a dynamic pattern of pathology was shown. The
- cortical thickness and area of CA1 and CA3 cells declined significantly as early as 1 week post-exposure. No
- pathological findings were detected following DFP and metrazol administration. It is therefore suggested
- that brain lesions are not common for all ChE inhibitors and that convulsions per se are not the only factor
- leading to brain damage following the administration of soman. The degenerative process (found also with the
- sublethal dose of soman) might be due to a secondary effect, unrelated to soman's clinical toxicity, but leading
- to long-term brain injuries. 42. J Neurotrauma. 1997 Dec;14(12):897-905.<strong> Effect of
- tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain
- injury. </strong>Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG. Department of Psychology, Virginia
- Commonwealth University, Medical College of Virginia, Richmond 23284-2018, USA. An emerging literature exists in
- support of deficits in cholinergic neurotransmission days to weeks following experimental traumatic brain injury
- (TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to improve cognitive outcome
- following TBI in rats. We examined the effects of repeated postinjury administration of a cholinesterase
- inhibitor, tetrahydroaminoacridine (THA), on cognitive performance following experimental TBI. Rats were either
- injured at a moderate level of central fluid percussion TBI (2.1+/-0.1 atm) or were surgically prepared but not
- delivered a fluid pulse (sham injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily
- for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0
- <hr />
- respectively). Cognitive performance was assessed on Days 11-15 after injury in a Morris water maze
- (MWM). <span><strong>Analysis of maze latencies over days indicated that</strong></span>
- <span><strong>chronic administration of THA produced a dose-related impairment in MWM</strong></span>
- <span><strong>performance in both the injured and sham groups, with the 9.0 mg/kg dose</strong></span>
- <span><strong>producing the largest deficit. T</strong></span>he 1.0 and 3.0 mg/kg doses of THA impaired MWM
- performance without affecting swimming speeds. Thus, the results of this investigation do not support the use of
- THA as a cholinomimetic therapeutic for the treatment of cognitive deficits following TBI. 43. Toxicol Lett.
- 1998 Dec 28;102-103:527-33. Chronic effects of low level exposure to anticholinesterases--a mechanistic review.
- Ray DE. Medical Research Council Toxicology Unit, Leicester, UK. <a
- href="mailto:der2@le.ac.uk"
- target="_blank"
- >der2@le.ac.uk</a>
- High dose exposure to anticholinesterases which results in symptomatic poisoning can have lasting
- consequences due to the trauma of intoxication, excitotoxicity, secondary hypoxic damage, and (for some
- agents) a delayed onset polyneuropathy (OPIDN). The potential effects of low level exposure are less well
- defined. The most reliable data comes from controlled clinical trials with specific agents. A single dose
- of sarin or repeated doses of metrifonate or mevinphos, have produced only transient adverse effects at doses
- causing substantial acetylcholinesterase inhibition. Other data comes from epidemiological surveys. These
- have often used more sensitive indices than the clinical studies, but are less reliable due to the
- difficulty of defining exposure and matching control and exposed populations. Subtle, mainly cognitive,
- differences between exposed and non-exposed populations are sometimes seen. Low level exposure can cause a
- reversible down-regulation of cholinergic systems, and a range of non-cholinesterase effects that are
- structure-specific, and do not always parallel acute toxicity. Novel protein targets sensitive to low level
- exposure to some organophosphates are known to exist in the brain, but their functional significance is not yet
- understood. 44. Exp Neurol. 2000 Nov;166(1):136-52. Postinjury administration of L-deprenyl improves cognitive
- function and enhances neuroplasticity after traumatic brain injury. Zhu J, Hamm RJ, Reeves TM, Povlishock
- JT, Phillips LL. Department of Anatomy, Medical College of Virginia, Richmond, Virginia 23298-0709, USA. The rat
- model of combined central fluid percussion traumatic brain injury (TBI) and bilateral entorhinal cortical lesion
- (BEC) produces profound, persistent cognitive deficits, sequelae associated with human TBI. In contrast to
- percussive TBI alone, this combined injury induces maladaptive hippocampal plasticity. Recent reports suggest a
- potential role for dopamine in CNS plasticity after trauma. We have examined the effect of the dopamine enhancer
- l-deprenyl on cognitive function and neuroplasticity following TBI. Rats received fluid percussion TBI, BEC
- alone, or combined TBI + BEC lesion and were treated once daily for 7 days with l-deprenyl, beginning 24 h after
- TBI alone and 15 min after BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl
- treatment. Cognitive performance was assessed on days 11-15 postinjury and brains from the same cases examined
- for dopamine beta-hydroxylase immunoreactivity (DBH-IR) and acetylcholinesterase (AChE) histochemistry.
- Significant cognitive improvement relative to untreated injured cases was observed in both TBI groups following
- l-deprenyl treatment; however, no drug effects were seen with BEC alone. l-Deprenyl attenuated injury-induced
- loss in DBH-IR over CA1 and CA3 after TBI alone. However, after combined TBI + BEC, l-deprenyl was only
- effective in protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with l-deprenyl
- in both injury models. <strong>After TBI + BEC, l-deprenyl also increased AChE</strong>
- <strong>in the dentate molecular layer relative to untreated injured cases. These results</strong>
- <strong>suggest that dopaminergic/noradrenergic enhancement facilitates cognitive</strong>
- recovery after brain injury and that noradrenergic fiber integrity is correlated with enhanced synaptic
- plasticity in the injured hippocampus. Copyright 2000 Academic Press. J Neurotrauma. 1992 May;9 Suppl
- 2:S463-74. <strong>Cholinergic and opioid mediation of traumatic brain injury.</strong> Lyeth BG,
- Hayes RL. Psychosom Med. 1976 Jan-Feb;38(1):55-8.<strong> Sudden death in the laboratory rat. </strong
- >Rosellini RA, Binik YM, Seligman MP. Vulnerability to sudden death was produced in laboratory rats by
- manipulating their developmental history. Rats who were reared in isolation died suddenly when placed in a
- stressful swimming situation. Handling of these singly-housed rats from 25 to 100 days of age potentiated the
- phenomenon. However, animals who were group housed did not die even when they had been previously handled.
- J Neurol Neurosurg Psychiatry. 1973 Aug;36(4):581-4. Creutzfeldt-Jakob disease treated with amantidine. A report
- of two cases. Sanders WL, Dunn TL. The treatment of two cases of Creutzfeldt-Jakob disease with amantidine is
- described. The first case made a remarkable initial improvement which was sustained for two months, but then
- deteriorated and died. Histological examination of the brain showed changes consistent with early
- Creutzfeldt-Jakob disease. The second case which was clinically one of Creutzfeldt-Jakob disease has now been
- followed for 30 months since the start of treatment and appears to be cured. It is considered that amantidine
- has a definite effect in this disease and it is suggested that its mode of action, though unknown, is more
- likely to be metabolic than antiviral. Free PMC Article Arch Int Pharmacodyn Ther. 1986 Mar;280(1):136-44.
- Effect of stress and glucocorticoids on the gastrointestinal cholinergic enzymes. Oriaku ET, Soliman KF.
- (Glucocorticoids lower AChE) Cardiovasc Res. 1990 Apr;24(4):335-9. Sympathectomy alters acetylcholinesterase
- expression in adult rat heart. Nyquist Battie C, Moran N. Harris LW, Garry VF, Jr, Moore RD. Biosynthesis
- of cholinesterase in rabbit bone marrow cells in culture. Biochem Pharmacol. 1974 Aug;23(15):2155–2163.
- Heller M, Hanahan DJ. Human erythrocyte membrane bound enzyme acetylcholinesterase. Biochim
- Biophys Acta. 1972 Jan 17;255(1):251–272. J Cell Biol. 1976 June 1; 69(3): 638–646. Bartos EM. Properties
- of growth-related acetylcholinesterase in a cell line of fibroblastic origin Behav Brain Res 2000
- Jul;112(1-2):33-41 Impaired escape performance and enhanced conditioned fear in rats following exposure to an
- uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus. Grahn RE,
- Watkins LR, Maier SF. Department of Psychology, Connecticut College, Box 5275, 270 Mohegan Avenue, 06320-4196,
- New London, CT 06320-4196, USA. <a href="mailto:regra@conncoll.edu" target="_blank">regra@conncoll.edu</a>
- Exposure to uncontrollable aversive events produces a variety of behavioral consequences that do not occur if
- the aversive event is controllable. Accumulating evidence suggests that exaggerated excitation of serotonin
- (5-HT) neurons in the dorsal raphe nucleus (DRN) is sufficient to cause these same behaviors, such as poor
- shuttlebox escape performance and enhanced conditioned fear that occur 24 h after exposure to inescapable
- tailshock (IS). The aim of the present studies was to explore the possibility that N-methyl-D-aspartate (NMDA)
- receptor activation and nitric oxide (NO) formation within the DRN might be involved in mediating the behavioral
- consequences of IS. To this end, either the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or
- the nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME), was microinjected into the DRN
- before IS or before testing 24 h later. Blocking NMDA receptors with APV in the DRN during IS prevented the
- usual impact of IS on escape responding and conditioned fear. However, injection of APV at the time of testing
- only reduced these effects. The DRN was shown to be the critical site mediating blockade of these behavioral
- changes since injection of APV lateral to the DRN did not alter the behavioral consequences of IS. Conversely,
- L-NAME was most effective in reversing the effects of IS when administered at the time of testing. These results
- suggest that there is glutamatergic input to the DRN at the time of IS that produces long-lasting changes in DRN
- sensitivity. This plasticity in the DRN is discussed as a possible mechanism by which IS leads to changes in
- escape performance and conditioned fear responding. and prolonged depression causes shrinkage of this area. The
- high cortisol associated with depression is undoubtedly one of the factors causing brain shrinkage during
- stress. Cushing's disease, in which the adrenal glands produce far too much cortisol, causes shrinkage of the
- brain, and when the disease is cured by normalizing the level of cortisol, the brain size is restored. There are
- two very different kinds of stress reaction. The best known "fight or flight reaction" could be called more
- accurately "struggle to adapt." Another, less discussed kind, might appear to be a "give up and die or get
- depressed" reaction, but it involves many processes that are protective and adaptive in certain circumstances.
- tone and heart rate; drown easily. The role of acetylcholine, (Anisman, et al., 1981). A situation of
- extreme restraint causes very rapid damage to the tissues, with bleeding ulcers of the stomach and intestine,
- shrinking of the thymus gland, and, if the animal survives for a while, atrophy of the brain. (Doi, et al.,
- 1991; Gatón, et al., 1993) LH, somatotropin, GH, Ach. caffeine progest Behav Brain Res. 2012 Mar
- 17;228(2):294-8. doi: 10.1016/j.bbr.2011.11.036. Epub 2011 Dec 8. Parental enrichment and offspring development:
- modifications to brain, behavior and the epigenome. Mychasiuk R, Zahir S, Schmold N, Ilnytskyy S, Kovalchuk O,
- Gibb R. University of Lethbridge, Canadian Centre for Behavioural Neuroscience, Canada.
- <a href="mailto:r.mychasiuk@uleth.ca" target="_blank">r.mychasiuk@uleth.ca</a>
-
- 4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi: 10.1016/j.biopha.2011.11.005. Epub 2011 Dec 21.
- Cholinesterase activities and biochemical determinations in patients with prostate cancer: influence of Gleason
- score, treatment and bone metastasis. Battisti V, Bagatini MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF,
- Abdalla FH, Battisti IE, Schetinger MR, Morsch VM. Departamento de Química, Centro de Ciências Naturais e
- Exatas, Universidade Federal de Santa Maria, Campus Universitário, 97105-900 Santa Maria, RS, Brazil.
- <a href="mailto:battistivanessa@gmail.com" target="_blank">battistivanessa@gmail.com</a>
- Prostate cancer (PCa) is the sixth most common type of cancer worldwide. Cholinesterase is well known as having
- non-cholinergic functions such as cellular proliferation and differentiation, suggesting a possible influence of
- cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate the whole blood
- acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) activities and some biochemical parameters
- in PCa patients. This study was performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
- were determined in PCa patients and the influence of the Gleason score; bone metastasis and treatment in the
- enzyme activities were also verified. Furthermore, we also analyzed possible biochemical alterations in these
- patients.
- <strong>AChE and BChE activities decreased in PCa patients in relation to the control</strong>
- <strong>group and various biochemical changes were observed in these patients. Moreover, </strong>
- <strong>Gleason score, metastasis and treatment influenced cholinesterase activities and </strong>
- <strong>biochemical determinations. Our results suggest that cholinesterases activities</strong>
- <strong>and biochemical parameters are altered in PCa. These facts support the idea that </strong>
- <strong>t</strong>he drop in the cholinesterase activity and the consequent increased amount of acetylcholine
- could lead to a cholinergic overstimulation and increase the cell proliferation in PCa. Copyright © 2011
- Elsevier Masson SAS. All rights reserved. 4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi:
- 10.1016/j.biopha.2011.11.005. Epub 2011 Dec 21. Cholinesterase activities and biochemical determinations in
- patients with prostate cancer: influence of Gleason score, treatment and bone metastasis. Battisti V, Bagatini
- MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF, Abdalla FH, Battisti IE, Schetinger MR, Morsch VM.
- Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus
- Universitário, 97105-900 Santa Maria, RS, Brazil.
- <a href="mailto:battistivanessa@gmail.com" target="_blank">battistivanessa@gmail.com</a>
- Prostate cancer (PCa) is the sixth most common type of cancer worldwide. Cholinesterase is well known as having
- non-cholinergic functions such as cellular proliferation and differentiation, suggesting a possible influence of
- cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate the whole blood
- acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) activities and some biochemical parameters
- in PCa patients. This study was performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
- were determined in PCa patients and the influence of the Gleason score; bone metastasis and treatment in the
- enzyme activities were also verified. Furthermore, we also analyzed possible biochemical alterations in these
- patients. AChE and BChE activities decreased in PCa patients in relation to the control group and various
- biochemical changes were observed in these patients. Moreover, Gleason score, metastasis and treatment
- influenced cholinesterase activities and biochemical determinations. Our results suggest that
- cholinesterases activities and biochemical parameters are altered in PCa. These facts support the idea
- that the drop in the cholinesterase activity and the consequent increased amount of acetylcholine could
- lead to a cholinergic overstimulation and increase the cell proliferation in PCa. Copyright © 2011 Elsevier
- Masson SAS. All rights reserved. 1. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 May;28(3):253-4, 262.
- [Progesterone exerts neuroprotective effect on hypoxic-ischemic encephalopathy-induced brain damage via
- inhibition expression of inducible nitric oxide synthase and nitric oxide production]. [Article in Chinese] Wang
- XY, Li XJ, Li DL, Wang CR, Guo XP.
- <a href="mailto:wxyinwxyin@163.com" target="_blank">wxyinwxyin@163.com</a>
-
- 2. Mol Reprod Dev. 2012 Oct;79(10):689-96. doi: 10.1002/mrd.22075. Epub 2012 Sep 11. Roles of cytokines and
- progesterone in the regulation of the nitric oxide generating system in bovine luteal endothelial cells.
- Yoshioka S, Acosta TJ, Okuda K. Laboratory of Reproductive Physiology, Graduate School of Natural Science and
- Technology, Okayama University, Okayama, Japan. Nitric oxide (NO) produced by luteal endothelial cells (LECs)
- plays important roles in regulating corpus luteum (CL) function, yet the local mechanism regulating NO
- generation in bovine CL remains unclear. The purpose of the present study was to elucidate if tumor necrosis
- factor-α (TNF), interferon γ (IFNG), and/or progesterone (P4) play roles in regulating NO generating system in
- LECs. Cultured bovine LECs obtained from the CL at the mid-luteal stage (Days 8-12 of the cycle) were treated
- for 24 hr with TNF (2.9 nM), IFNG (2.5 nM), or P4 (0.032-32 µM). NO production was increased by TNF and IFNG,
- but decreased by P4 (P < 0.05). TNF and IFNG stimulated the relative steady-state amounts of inducible nitric
- oxide synthase (iNOS) mRNA and iNOS protein expression (P < 0.05), whereas P4 inhibited relative steady-state
- amounts of iNOS mRNA and iNOS protein expression (P < 0.05). In contrast, endothelial nitric oxide synthase
- (eNOS) expression was not affected by any treatment. TNF and IFNG stimulated NOS activity (P < 0.05) and
- 1400W, a specific inhibitor of iNOS, reduced NO production stimulated by TNF and IFNG in LECs
- (P < 0.05)<strong>. Onapristone,</strong>
- <strong>a specific P4 receptor antagonist, blocked the inhibitory effect of P4 on NO</strong>
- production in LECs (P < 0.05). The overall findings suggest that TNF and IFNG accelerate luteolysis by
- increasing NO production via stimulation of iNOS expression and NOS activity in bovine LECs. P4, on the other
- hand, may act in maintaining CL function by suppressing iNOS expression in bovine LECs. Mol. Reprod. Dev. 79:
- 689-696, 2012. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc. 3. J Neurochem. 2012
- Jul;122(1):185-95. doi: 10.1111/j.1471-4159.2012.07753.x. Progesterone prevents mitochondrial dysfunction in the
- spinal cord of wobbler mice. Deniselle MC, Carreras MC, Garay L, Gargiulo-Monachelli G, Meyer M, Poderoso
- JJ, De Nicola AF. Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina
- Experimental-CONICET, Buenos Aires, Argentina. In the Wobbler mouse, a mutation of the Vps54 protein increases
- oxidative stress in spinal motoneurons, associated to toxic levels of nitric oxide and hyperactivity of
- nitric oxide synthase (NOS). Progesterone neuroprotection has been reported for several CNS diseases, including
- the Wobbler mouse neurodegeneration. In the present study, we analyzed progesterone effects on
- mitochondrial-associated parameters of symptomatic Wobbler mice. The activities of mitochondrial respiratory
- chain complexes I, II-III and IV and protein levels of mitochondrial and cytosolic NOS were determined in
- cervical and lumbar cords from control, Wobbler and Wobbler mice receiving a progesterone implant for 18 days.
- We found a significant reduction of complex I and II-III activities in mitochondria and increased protein levels
- of mitochondrial, but not cytosolic nNOS, in the cervical cord of Wobbler mice. <strong>Progesterone
- treatment prevented the </strong>
- <strong>reduction of complex I in the cervical region and the increased level of</strong>
- <strong>mitochondrial nNOS.</strong> Wobbler motoneurons also showed accumulation of amyloid precursor
- protein immunoreactivity and decreased activity and immunostaining of MnSOD. Progesterone treatment avoided
- these abnormalities. Therefore, administration of progesterone to clinically afflicted Wobblers (i) prevented
- the abnormal increase of mitochondrial nNOS and normalized respiratory complex I; (ii) decreased amyloid
- precursor protein accumulation, a sign of axonal degeneration, and (iii) increased superoxide dismutation. Thus,
- progesterone neuroprotection decreases mitochondriopathy of Wobbler mouse cervical spinal cord. © 2012 The
- Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry. Comp Biochem Physiol C. 1993
- Sep;106(1):125-9.<strong> The role of the neurotransmitters acetylcholine and noradrenaline in the
- pathogenesis of stress ulcers. </strong>Gatón J, Fernández de la Gándara F, Velasco A. People with
- Cloninger's "harm avoidance" personality trait, which is closely associated with serotonin (Hansenne, et al.,
- 1999), are more likely to develop dementia (Clément, et al., 2010). These observations are consistent with the
- stress-susceptibility of people with high serotonin exposure, and to the effects of cortisol on nerves and
- glucose-derived energy production. Jpn J Surg. 1991 Jan;21(1):43-9.
- <strong>Participation of the parasympathetic nervous system in the development of</strong>
- <strong>activity-stress ulcers.</strong>
- Doi K, Iwahashi K, Tsunekawa K.17. J Auton Nerv Syst. 1987 Oct;20(3):265-8. Adrenergic modulation of gastric
- stress pathology in rats: a cholinergic link. Ray A, Sullivan RM, Henke PG. Department of Psychology, St.
- Francis Xavier University, Antigonish, Nova Scotia, Canada. The effects of some adrenergic drugs were evaluated
- on cold restraint-induced gastric ulcers in rats. The beta-adrenergic antagonist, (+/-)-propranolol (1 and
- 10 mg/kg), as well as the beta-agonist, isoproterenol (0.05 and 0.5 mg/kg) potentiated the gastric pathology. On
- the other hand, the alpha-agonist, clonidine (0.5 mg/kg) attenuated and the alpha-antagonist, yohimbine (1
- mg/kg) aggravated stress ulcer development. The anticholinergic agent, atropine methylnitrate (1 mg/kg), reduced
- both the frequency and severity of stress ulcers and also antagonized the potentiating effects of
- (+/-)-propranolol, isoproterenol and yohimbine. The results suggest a cholinergic role in the adrenergic
- modulation of gastric stress pathology. Psychopharmacology (Berl). 1981;74(1):81-7.
- <strong>Cholinergic influences on escape deficits produced by uncontrollable stress.</strong>
- Anisman H, Glazier SJ, Sklar LS. A series of experiments assessed the potential role of acetylcholine (ACh) in
- the escape interference produced by inescapable shock. <strong>Treatment with the</strong>
- <strong>anticholinesterase, physostigmine, successfully mimicked the effects of</strong>
- <strong>inescapable shock. </strong>That is, the drug disrupted performance when escape was prevented for 6
- s on any given trial, thereby necessitating sustained active responding. When escape was possible upon shock
- onset, the drug treatment did not influence performance. <strong>The centrally acting anticholinergic
- scopolamine</strong>
- <strong>hydrobromide antagonized the effects of physostigmine, and when administered</strong>
- <strong>prior to escape testing antagonized the disruptive effects of previously</strong>
- <strong>administered inescapable shock.</strong> In contrast, the peripherally acting agent scopolamine
- methylbromide did not influence the effects of these treatments, suggesting that the effects of physostigmine
- and inescapable shock involved central ACh changes. Scopolamine hydrobromide administered prior to inescapable
- shock did not prevent the escape interference from subsequently appearing, but this effect could not be
- attributed to state dependence. It was argued that the interference of escape following uncontrollable stress
- was due to non-associative motor deficits. Alterations of the escape deficits by scopolamine were due to
- elimination of the motor disruption. Curr Opin Oncol. 2005 Jan;17(1):55-60. DNA methylation and cancer therapy:
- new developments and expectations. Esteller M. Cancer Epigenetics Laboratory, Spanish National Cancer Centre
- (CNIO) Madrid, Spain. <a href="mailto:mesteller@cnio.es" target="_blank">mesteller@cnio.es</a>
- PURPOSE OF REVIEW: In addition to having genetic causes, cancer can also be considered an epigenetic disease.
- The main epigenetic modification is DNA methylation, and patterns of aberrant DNA methylation are now recognized
- to be a common hallmark of human tumors. One of the most characteristic features is the inactivation of
- tumor-suppressor genes by CpG-island hypermethylation of the CpG islands located in their promoter
- regions. These sites, among others, are the targets of DNA-demethylating agents, the promising chemotherapeutic
- drugs that are the focus of this article. RECENT FINDINGS: Four exciting aspects have recently arisen at the
- forefront of the advancements in this field: first, the development of new compounds with DNA-demethylating
- capacity that are less toxic (for example, procaine) and may be administered orally (for example,
- zebularine); Science. 2013 May 10;340(6133):756-9.
- <strong>Emergence of individuality in genetically identical mice.</strong>
- Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzler M, Krüger A, Sachser N, Lindenberger U, Kempermann G.
- CRTD-DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
- Comment in Science. 2013 May 10;340(6133):695-6. Brain plasticity as a neurobiological reflection
- of individuality is difficult to capture in animal models. Inspired by behavioral-genetic investigations of
- human monozygotic twins reared together, we obtained dense longitudinal activity data on 40 inbred mice
- living in one large enriched environment. The exploratory activity of the mice diverged over time, resulting in
- increasing individual differences with advancing age. Individual differences in cumulative roaming entropy,
- indicating the active coverage of territory, correlated positively with individual differences in adult
- hippocampal neurogenesis. Our results show that factors unfolding or emerging during development contribute to
- individual differences in structural brain plasticity and behavior. The paradigm introduced here serves as
- an animal model for identifying mechanisms of plasticity underlying nonshared environmental contributions to
- individual differences in behavior. Neurobiol Aging. 1995 Jul-Aug;16(4):523-30. Delayed onset of Alzheimer's
- disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Breitner JC, Welsh KA, Helms MJ,
- Gaskell PC, Gau BA, Roses AD, Pericak-Vance MA, Saunders AM. If each opportunity we have to choose expands
- our curiosity, we go beyond our inheritance to become something unique but also universal, that is, more
- fully human. J Neurobiol. 1976 Jan;7(1):75-85. Effects of environment on morphology of rat cerebral cortex and
- hippocampus. Diamond MC, Ingham CA, Johnson RE, Bennett EL, Rosenzweig MR. … strains of rats. KRECH D,
- ROSENZWEIG MR, BENNETT EL.… 19. Pharmacol Biochem Behav. 1986 Sep;25(3):521-6. Cholinergic function and memory:
- extensive inhibition of choline acetyltransferase fails to impair radial maze performance in rats. Wenk G,
- Sweeney J, Hughey D, Carson J, Olton D. The present study investigated the effects of a potent inhibitor of
- choline acetyltransferase (ChAT), BW813U, on the choice accuracy of rats in the radial arm maze. BW813U (100
- mg/kg, IP) produced a rapid (within 1 hour) and substantial decrease in ChAT activity throughout the brain,
- ranging from 66% (hippocampus) to 80% (caudate nucleus) that lasted up to 5 days. <strong>A single
- injection (50 mg/kg, IP)</strong>
- <strong>into rats with lesions (using ibotenic acid) in the nucleus basalis</strong>
- <strong>magnocellularis and medial septal area, decreased ChAT activity by 75% and 60% in</strong>
- <strong>the cortex and hippocampus, respectively. Lesioned and unlesioned rats were</strong>
- <strong>trained on the radial arm maze until they reached a criterion level of</strong>
- <strong>performance. </strong>Each rat then received an injection of BW813U (50 or 100 mg/kg, IP). Choice
- accuracy was not impaired at any time following the injection. The lack of effect on performance may be due to 2
- possible factors: The radial maze retention paradigm chosen may not be sufficiently difficult, or the decrease
- in acetylcholine production was not sufficient to affect behavior. Compensation by non-cholinergic neural
- systems might account for the insensitivity of the rats to significant cholinergic depletion. Psychol Aging.
- 1988 Dec;3(4):399-406. Genotype-environment interaction in personality development: identical twins reared
- apart. Bergeman CS, Plomin R, McClearn GE, Pedersen NL, Friberg LT. Center for Developmental and Health
- Genetics, Pennsylvania State University, University Park 16802. The focus of this study is to identify specific
- genotype-environment (GE) interactions as they contribute to individual differences in personality in later
- life. In behavioral genetics, GE interaction refers to the possibility that individuals of different genotypes
- may respond differently to specific environments. A sample of 99 pairs of identical twins reared apart, whose
- average age is 59 years, has been studied as part of the Swedish Adoption/Twin Study of Aging (SATSA).
- Hierarchical multiple regression was used to detect interactions between personality and environmental measures
- after the main effects of genotype and environment were removed. Analyses yield evidence for 11 significant
- interactions that provide the first evidence for GE interaction in human development using specific
- environmental measures. Thus, in addition to the main-effect contributions of heredity and environment, GE
- interactions contribute to individual differences in personality as measured in the second half of the life
- course.
-
- <span>Wikipedia:</span>
- <strong>Excitability and inhibition</strong>
- <span>[<a
- href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&action=edit&section=8"
- target="_blank"
- ><span>edit source</span></a> | <a
- href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&veaction=edit&section=8"
- target="_blank"
- ><span>edit</span><span>beta</span></a>]</span>
- <p>
- Acetylcholine also has other effects on neurons. One effect is to cause a slow <a
- href="http://en.wikipedia.org/wiki/Depolarization"
- target="_blank"
- ><span>depolarization</span></a>
- <span><sup>[</sup><a href="http://en.wikipedia.org/wiki/Wikipedia:Citation_needed" target="_blank"><span><em
- >citation needed</em></span></a><sup>]</sup></span> by blocking a tonically active K<span
- >+</span>
- <span></span> current, which increases neuronal excitability. Alternatively, acetylcholine can activate
- non-specific cation conductances to directly excite neurons.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Haj-Dahmane-10"
- target="_blank"
- ><span>[10]</span></a> An effect upon postsynaptic <a
- href="http://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4"
- target="_blank"
- ><span>M4-muscarinic ACh receptors</span></a> is to open <a
- href="http://en.wikipedia.org/wiki/Inward-rectifier_potassium_ion_channel"
- target="_blank"
- ><span>inward-rectifier potassium ion channel</span></a> (K<span><sub>ir</sub></span>) and cause
- inhibition.<a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Eggermann-11" target="_blank"><span
- >[11]</span></a> The influence of acetylcholine on specific neuron types can be dependent upon the
- duration of cholinergic stimulation. For instance, transient exposure to acetylcholine (up to several
- seconds) can inhibit cortical pyramidal neurons via M1 type muscarinic receptors that are linked to Gq-type
- G-protein alpha subunits. <strong>M1 receptor activation can induce calcium-release from intracellular
- stores, which then activate a calcium-activated potassium conductance which inhibits </strong
- >pyramidal neuron firing.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gulledge1-12"
- target="_blank"
- ><span>[12]</span></a> <strong>On the other hand, tonic M1 receptor activation is strongly
- excitatory. </strong>Thus, ACh acting at one type of receptor can have multiple effects on the same
- postsynaptic neuron, depending on the duration of receptor activation.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gulledge2-13"
- target="_blank"
- ><span>[13]</span></a> Recent experiments in behaving animals have demonstrated that cortical neurons
- indeed experience both transient and persistent changes in local acetylcholine levels during cue-detection
- behaviors.<a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Sarter1-14" target="_blank"><span
- >[14]</span></a>
- </p>
- <p>
- In the cerebral cortex, tonic ACh inhibits layer 4 <a
- href="http://en.wikipedia.org/wiki/Medium_spiny_neuron"
- target="_blank"
- ><span>medium spiny neurons</span></a>, the main targets of thalamocortical inputs while exciting<a
- href="http://en.wikipedia.org/wiki/Pyramidal_cell"
- target="_blank"
- ><span>pyramidal cells</span></a> in layers 2/3 and layer 5.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Eggermann-11"
- target="_blank"
- ><span>[11]</span></a> This filters out weak sensory inputs in layer 4 and amplifies inputs that reach
- the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACh might
- function to improve the signal noise ratio of cortical processing.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Eggermann-11"
- target="_blank"
- ><span>[11]</span></a> At the same time, acetylcholine acts through nicotinic receptors to excite
- certain groups of inhibitory interneurons in the cortex, which further dampen down cortical activity.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gulledge3-15"
- target="_blank"
- ><span>[15]</span></a>
- </p>
- <p>
- <strong>Role in decision making</strong>
- <span>[<a
- href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&action=edit&section=9"
- target="_blank"
- ><span>edit source</span></a> | <a
- href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&veaction=edit&section=9"
- target="_blank"
- ><span>edit</span><span>beta</span></a>]</span>
- </p>
- <p>
- One well-supported function of acetylcholine (ACh) in cortex is increased responsiveness to sensory stimuli,
- a form of <a href="http://en.wikipedia.org/wiki/Attention" target="_blank"><span>attention</span></a
- >.<a
- href="http://en.wikipedia.org/w/index.php?title=Phasic&action=edit&redlink=1"
- target="_blank"
- ><span>Phasic</span></a> increases of ACh during visual,<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-16"
- target="_blank"
- ><span>[16]</span></a> auditory <a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-17"
- target="_blank"
- ><span>[17]</span></a> and somatosensory <a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-18"
- target="_blank"
- ><span>[18]</span></a> stimulus presentations have been found to increase the firing rate of neurons in
- the corresponding primary sensory cortices. When cholinergic neurons in the basal forebrain are lesioned,
- animals' ability to detect visual signals was robustly and persistently impaired.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-19"
- target="_blank"
- ><span>[19]</span></a> In that same study, animals' ability to correctly reject non-target trials was
- not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli.
- Looking at ACh's effect on thalamocortical connections, a known pathway of sensory information, in vitro
- application of cholinergic <a href="http://en.wikipedia.org/wiki/Agonist" target="_blank"><span
- >agonist</span></a> <a href="http://en.wikipedia.org/wiki/Carbachol" target="_blank"><span
- >carbachol</span></a> to mouse auditory cortex enhanced thalamocortical activity.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Hsieh-20"
- target="_blank"
- ><span>[20]</span></a> In addition, Gil et al. (1997) applied a different cholinergic agonist, <a
- href="http://en.wikipedia.org/wiki/Nicotine"
- target="_blank"
- ><span>nicotine</span></a>, and found that activity was enhanced at thalamocortical synapses.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gil-21"
- target="_blank"
- ><span>[21]</span></a>This finding provides further evidence for a facilitative role of ACh in transmission
- of sensory information from the thalamus to selective regions of cortex.
- </p>
- <p>
- An additional suggested function of ACh in cortex is suppression of intracortical information transmission.
- Gil et al. (1997) applied the cholinergic agonist <a
- href="http://en.wikipedia.org/wiki/Muscarine"
- target="_blank"
- ><span>muscarine</span></a> to neocortical layers and found that <a
- href="http://en.wikipedia.org/wiki/Excitatory_post-synaptic_potentials"
- target="_blank"
- ><span>excitatory post-synaptic potentials</span></a> between intracortical synapses were depressed.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gil-21"
- target="_blank"
- ><span>[21]</span></a> In vitro application of cholinergic agonist carbachol to mouse auditory cortex
- suppressed intracortical activity as well.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Hsieh-20"
- target="_blank"
- ><span>[20]</span></a> Optical recording with a voltage-sensitive dye in rat visual cortical slices
- demonstrated significant suppression in intracortical spread of excitement in the presence of ACh.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-22"
- target="_blank"
- ><span>[22]</span></a>
- </p>
- <p>
- Some forms of learning and plasticity in cortex appear dependent on the presence of acetylcholine. Bear et
- al. (1986) found that the typical synaptic remapping in <a
- href="http://en.wikipedia.org/wiki/Striate_cortex"
- target="_blank"
- ><span>striate cortex</span></a> that occurs during <a
- href="http://en.wikipedia.org/wiki/Monocular_deprivation"
- target="_blank"
- ><span>monocular deprivation</span></a> is reduced when there is a depletion of cholinergic projections
- to that region of cortex.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-23"
- target="_blank"
- ><span>[23]</span></a> Kilgard et al. (1998) found that repeated stimulation of the <a
- href="http://en.wikipedia.org/wiki/Basal_forebrain"
- target="_blank"
- ><span>basal forebrain</span></a>, a primary source of ACh neurons, paired with presentation of a tone at a
- specific frequency, resulted in remapping of the <a
- href="http://en.wikipedia.org/wiki/Auditory_cortex"
- target="_blank"
- ><span>auditory cortex</span></a> to better suit processing of that tone.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-24"
- target="_blank"
- ><span>[24]</span></a>Baskerville et al. (1996) investigated the role of ACh in <a
- href="http://en.wikipedia.org/w/index.php?title=Experience-dependent_plasticity&action=edit&redlink=1"
- target="_blank"
- ><span>experience-dependent plasticity</span></a> by depleting cholinergic inputs to the <a
- href="http://en.wikipedia.org/wiki/Barrel_cortex"
- target="_blank"
- ><span>barrel cortex</span></a> of rats.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-25"
- target="_blank"
- ><span>[25]</span></a> The cholinergic depleted animals had a significantly reduced amount of
- whisker-pairing plasticity. Apart from the cortical areas, Crespo et al. (2006) found that the activation of
- nicotinic and muscarinic receptors in the <a
- href="http://en.wikipedia.org/wiki/Nucleus_accumbens"
- target="_blank"
- ><span>nucleus accumbens</span></a> is necessary for the acquisition of an appetitive task.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-achcorrelation-26"
- target="_blank"
- ><span>[26]</span></a>
- </p>
- <p>
- ACh has been implicated in the reporting of expected uncertainty in the environment <a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-27"
- target="_blank"
- ><span>[27]</span></a> based both on the suggested functions listed above and results recorded while
- subjects perform a behavioral cuing task. <a
- href="http://en.wikipedia.org/wiki/Reaction_time"
- target="_blank"
- ><span>Reaction time</span></a> difference between correctly cued trials and incorrectly cued
- trials, <span><strong>called the cue validity, was found to vary inversely with ACh </strong
- ></span>levels in primates with pharmacologically (e.g. Witte et al., 1997) and surgically (e.g. Voytko
- et al., 1994) altered levels of ACh.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-28"
- target="_blank"
- ><span>[28]</span></a>
- <a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-29" target="_blank"><span>[29]</span></a
- > The result was also found in <a
- href="http://en.wikipedia.org/wiki/Alzheimer%27s_disease"
- target="_blank"
- ><span>Alzheimer's disease</span></a> patients (Parasuraman et al., 1992) and smokers after nicotine
- (an ACh agonist) consumption.<a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-30"
- target="_blank"
- ><span>[30]</span></a>
- <a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-31" target="_blank"><span>[31]</span></a
- > The inverse covariance is consistent with the interpretation of ACh as representing expected
- uncertainty in the environment, further supporting this claim.
- </p>
-
- <li>
- <span><strong>12•.</strong><a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Gulledge1_12-0"
- target="_blank"
- ><strong>^</strong></a></span> Gulledge, AT; Stuart, GJ (2005). "Cholinergic inhibition of
- neocortical pyramidal neurons". <em>Journal of Neuroscience</em> <strong>25</strong> (44):
- 10308–20. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" target="_blank"><span
- >doi</span></a>:<a href="http://dx.doi.org/10.1523%2FJNEUROSCI.2697-05.2005" target="_blank"><span
- >10.1523/JNEUROSCI.2697-05.2005</span></a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/16267239" target="_blank"><span
- >16267239</span></a>.
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Gulledge2_13-0" target="_blank"><strong
- >^</strong></a></span>
- <span> Gulledge, AT; Bucci, DJ; Zhang, SS; Matsui, M; Yeh, HH (2009). <a
- href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745329"
- target="_blank"
- >"M1 Receptors Mediate Cholinergic Modulation of Excitability in Neocortical Pyramidal Neurons"</a
- >. <em>Journal of Neuroscience</em> <strong>29</strong> (31): 9888–902. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1523%2FJNEUROSCI.1366-09.2009" target="_blank"
- >10.1523/JNEUROSCI.1366-09.2009</a>.<a
- href="http://en.wikipedia.org/wiki/PubMed_Central"
- target="_blank"
- ><span>PMC</span></a> <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745329" target="_blank"
- >2745329</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" target="_blank"><span
- >PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/19657040" target="_blank"
- >19657040</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Sarter1_14-0" target="_blank"><strong
- >^</strong></a></span>
- <span> Parikh, V; Kozak, R; Martinez, V; Sarter, M (2007). <a
- href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2084212"
- target="_blank"
- >"Prefrontal acetylcholine release controls cue detection on multiple time scales"</a>. <em
- >Neuron</em> <strong>56</strong> (1): 141–54. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1016%2Fj.neuron.2007.08.025" target="_blank"
- >10.1016/j.neuron.2007.08.025</a>.<a
- href="http://en.wikipedia.org/wiki/PubMed_Central"
- target="_blank"
- ><span>PMC</span></a> <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2084212" target="_blank"
- >2084212</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" target="_blank"><span
- >PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/17920021" target="_blank"
- >17920021</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Gulledge3_15-0" target="_blank"><strong
- >^</strong></a></span> Gulledge, AT; Park, SB; Kawaguchi, Y; Stuart, GJ (2007). "Heterogeneity
- of phasic cholinergic signaling in neocortical neurons".<em>Journal of neurophysiology</em> <strong
- >97</strong> (3): 2215–29. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1152%2Fjn.00493.2006" target="_blank"><span
- >10.1152/jn.00493.2006</span></a>.<a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/17122323" target="_blank"><span
- >17122323</span></a>.
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-16" target="_blank"><strong>^</strong></a
- ></span>
- <span> Spehlmann R, Daniels JC, Smathers CC (1971). <a
- href="http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=4324030"
- target="_blank"
- >"Acetylcholine and the synaptic transmission of specific impulses to the visual cortex"</a>. <em
- >Brain</em> <strong>94</strong> (1): 125–38. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1093%2Fbrain%2F94.1.125" target="_blank"
- >10.1093/brain/94.1.125</a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/4324030" target="_blank"
- >4324030</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-17" target="_blank"><strong>^</strong></a
- ></span>
- <span> Foote SL, Freedman R, Oliver AP (March 1975). <a
- href="http://linkinghub.elsevier.com/retrieve/pii/0006-8993(75)90699-X"
- target="_blank"
- >"Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex"</a>. <em
- >Brain Res.</em> <strong>86</strong> (2): 229–42. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1016%2F0006-8993%2875%2990699-X" target="_blank"
- >10.1016/0006-8993(75)90699-X</a>.<a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/234774" target="_blank"
- >234774</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-18" target="_blank"><strong>^</strong></a
- ></span>
- <span> Stone TW (September 1972). <a
- href="http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=5074408"
- target="_blank"
- >"Cholinergic mechanisms in the rat somatosensory cerebral cortex"</a>. <em>J. Physiol. (Lond.)</em
- > <strong>225</strong> (2): 485–99. <a
- href="http://en.wikipedia.org/wiki/PubMed_Central"
- target="_blank"
- ><span>PMC</span></a> <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1331117" target="_blank"
- >1331117</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" target="_blank"><span
- >PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/5074408" target="_blank"
- >5074408</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-19" target="_blank"><strong>^</strong></a
- ></span>
- <span> McGaughy J, Kaiser T, Sarter M (April 1996). <a
- href="http://content.apa.org/pubmed/bne/110/2/247"
- target="_blank"
- >"Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of
- the behavioral impairment and relation to cortical AChE-positive fiber density"</a>. <em>Behav.
- Neurosci.</em> <strong>110</strong> (2): 247–65.<a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1037%2F0735-7044.110.2.247" target="_blank"
- >10.1037/0735-7044.110.2.247</a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/8731052" target="_blank"
- >8731052</a>.</span>
- </li>
- <li>
- <span>^ <a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Hsieh_20-0" target="_blank"><span
- ><strong><em>a</em></strong></span></a> <a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Hsieh_20-1"
- target="_blank"
- ><span><strong><em>b</em></strong></span></a> Hsieh CY, Cruikshank SJ, Metherate R (October
- 2000). <a href="http://linkinghub.elsevier.com/retrieve/pii/S0006-8993(00)02766-9" target="_blank"
- >"Differential modulation of auditory thalamocortical and intracortical synaptic transmission by
- cholinergic agonist"</a>. <em>Brain Res.</em> <strong>880</strong> (1–2): 51–64.<a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1016%2FS0006-8993%2800%2902766-9" target="_blank"
- >10.1016/S0006-8993(00)02766-9</a>.<a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/11032989" target="_blank"
- >11032989</a>.</span>
- </li>
- <li>
- <span>^ <a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Gil_21-0" target="_blank"><span
- ><strong><em>a</em></strong></span></a> <a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-Gil_21-1"
- target="_blank"
- ><span><strong><em>b</em></strong></span></a> Gil Z, Connors BW, Amitai Y (September 1997). <a
- href="http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(00)80380-3"
- target="_blank"
- >"Differential regulation of neocortical synapses by neuromodulators and activity"</a>. <em
- >Neuron</em> <strong>19</strong> (3): 679–86. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1016%2FS0896-6273%2800%2980380-3" target="_blank"
- >10.1016/S0896-6273(00)80380-3</a>.<a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/9331357" target="_blank"
- >9331357</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-22" target="_blank"><strong>^</strong></a
- ></span>
- <span> Kimura F, Fukuda M, Tsumoto T (October 1999). <a
- href="http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0953-816X&date=1999&volume=11&issue=10&spage=3597"
- target="_blank"
- >"Acetylcholine suppresses the spread of excitation in the visual cortex revealed by optical recording:
- possible differential effect depending on the source of input"</a>. <em>Eur. J. Neurosci.</em
- > <strong>11</strong> (10): 3597–609.<a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1046%2Fj.1460-9568.1999.00779.x" target="_blank"
- >10.1046/j.1460-9568.1999.00779.x</a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/10564367" target="_blank"
- >10564367</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-23" target="_blank"><strong>^</strong></a
- ></span> Bear MF, Singer W (1986). "Modulation of visual cortical plasticity by acetylcholine and
- noradrenaline". <em>Nature</em> <strong>320</strong> (6058): 172–6.<a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1038%2F320172a0" target="_blank"><span
- >10.1038/320172a0</span></a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/3005879" target="_blank"><span
- >3005879</span></a>.
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-24" target="_blank"><strong>^</strong></a
- ></span> Kilgard MP, Merzenich MM (March 1998). "Cortical map reorganization enabled by nucleus
- basalis activity". <em>Science</em> <strong>279</strong> (5357): 1714–8. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1126%2Fscience.279.5357.1714" target="_blank"><span
- >10.1126/science.279.5357.1714</span></a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/9497289" target="_blank"><span
- >9497289</span></a>.
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-25" target="_blank"><strong>^</strong></a
- ></span>
- <span> Baskerville KA, Schweitzer JB, Herron P (October 1997). <a
- href="http://linkinghub.elsevier.com/retrieve/pii/S030645229700064X"
- target="_blank"
- >"Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat"</a
- >. <em>Neuroscience</em> <strong>80</strong> (4): 1159–69. <a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1016%2FS0306-4522%2897%2900064-X" target="_blank"
- >10.1016/S0306-4522(97)00064-X</a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/9284068" target="_blank"
- >9284068</a>.</span>
- </li>
- <li>
- <span><a
- href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-achcorrelation_26-0"
- target="_blank"
- ><strong>^</strong></a></span>
- <span> Crespo JA, Sturm K, Saria A, Zernig G (May 2006). <a
- href="http://www.jneurosci.org/content/26/22/6004.full"
- target="_blank"
- >"Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens core is
- necessary for the acquisition of drug reinforcement"</a>.<em>J. Neurosci.</em> <strong
- >26</strong> (22): 6004–10.<a
- href="http://en.wikipedia.org/wiki/Digital_object_identifier"
- target="_blank"
- ><span>doi</span></a>:<a href="http://dx.doi.org/10.1523%2FJNEUROSCI.4494-05.2006" target="_blank"
- >10.1523/JNEUROSCI.4494-05.2006</a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/16738243" target="_blank"
- >16738243</a>.</span>
- </li>
- <li>
- <a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-27" target="_blank"><strong>^</strong></a>
- <span> <a href="http://en.wikipedia.org/wiki/Acetylcholine#CITEREFYuDayan2005" target="_blank"
- >Yu & Dayan 2005</a></span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-28" target="_blank"><strong>^</strong></a
- ></span>
- <span> Witte EA, Marrocco RT (August 1997). <a
- href="http://link.springer.de/link/service/journals/00213/bibs/7132004/71320315.htm"
- target="_blank"
- >"Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert
- orienting"</a>. <em>Psychopharmacology (Berl.)</em> <strong>132</strong> (4):
- 315–23.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" target="_blank"><span>doi</span
- ></a>:<a href="http://dx.doi.org/10.1007%2Fs002130050351" target="_blank"
- >10.1007/s002130050351</a>. <a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/9298508" target="_blank"
- >9298508</a>.</span>
- </li>
- <li>
- <span><a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_ref-29" target="_blank"><strong>^</strong></a
- ></span> Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL (January 1994). <a
- href="http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=8283232"
- target="_blank"
- ><span>"Basal forebrain lesions in monkeys disrupt attention but not learning and memory"</span></a
- >. <em>J. Neurosci.</em> <strong>14</strong> (1): 167–86.<a
- href="http://en.wikipedia.org/wiki/PubMed_Identifier"
- target="_blank"
- ><span>PMID</span></a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/8283232" target="_blank"><span
- >8283232</span></a>.
- </li>
-
- 1. Pharmacol Res. 2011 Jun;63(6):525-31. Endothelin receptor antagonists: potential in Alzheimer's
- disease. Palmer J, Love S. Dementia Research Group, Institute of Clinical Neurosciences, School of
- Clinical Sciences, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, United Kingdom. <a
- href="mailto:jen.palmer@bristol.ac.uk"
- target="_blank"
- >jen.palmer@bristol.ac.uk</a>
- Alzheimer's disease (AD) is believed to be initiated by the accumulation of neurotoxic forms of Aβ peptide
- within the brain. AD patients show reduction of cerebral blood flow (CBF), the extent of the reduction
- correlating with the impairment of cognition. <span><strong>There is evidence that cerebral hypoperfusion
- precedes</strong></span>
- <span><strong>and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs </strong
- ></span>
- <span><strong>neuronal function, reduces the clearance of Aβ peptide and other toxic</strong></span>
- <span><strong>metabolites from the brain, and upregulates Aβ production. Studies in animal</strong></span>
- <span><strong>models of AD have shown the reduction in CBF to be more than would be expected</strong></span>
- <span><strong>for the reduction in neuronal metabolic activity. </strong></span>Aβ may contribute to the
- reduction in CBF in AD, as both Aβ<span>₁₋₄₀</span> and Aβ<span>₁₋₄₂</span> induce cerebrovascular
- dysfunction. Aβ<span>₁₋₄₀</span> acts directly on cerebral arteries to cause cerebral smooth muscle cell
- contraction. Aβ<span>₁₋₄₂</span> causes increased neuronal production and release of endothelin-1
- (ET-1), a potent vasoconstrictor, and upregulation of endothelin-converting enzyme-2 (ECE-2), the enzyme which
- cleaves ET-1 from its inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that
- upregulation of the ECE-2-ET-1 axis by Aβ<span>₁₋₄₂</span> contributes to the chronic reduction of CBF in
- AD. At present, only a few symptomatic treatment options exist for AD. The involvement of ET-1 in the
- pathogenesis of endothelial dysfunction associated with elevated Aβ indicates the potential for endothelin
- receptor antagonists in the treatment of AD. It has already been demonstrated that the endothelin receptor
- antagonist bosentan, preserves aortic and carotid endothelial function in Tg2576 mice, and our findings suggest
- that endothelin receptor antagonists may be beneficial in maintaining CBF in AD. Copyright © 2011 Elsevier Ltd.
- All rights reserved. Fiziol Zh SSSR Im I M Sechenova. 1975 Oct;61(10):1466-72. [Amine receptors in brain
- vessels]. [Article in Russian] Edvinsson L, Owman Ch. Isolated middle cerebral arteries from cats and pial
- arteries from humans (obtained during lobe resection) were studied in a sensitive in vitro system allowing a
- detailed pharmacological characterization of various amine receptors and related dissociation constants. It was
- found that the adrenergic receptors comprise contractile (alpha) and dilatory (beta) receptors.<strong
- > Acetylcholine induced</strong>
- <strong>dilation (at low doses) as well as constriction (at high doses) both responses</strong>
- <strong>being inhibited in a comparative way by atropine.</strong> Experiments with selective inhibitors
- showed the presence of specific histamine H2 (dilatory) receptors; <strong>at </strong>
- <strong>high doses histamine contracted the vessels in a non-specific way.</strong>
- <strong>5-Hydroxytryptamine was the most efficient vasoconstrictor agent, and the</strong>
- response could be blocked by the serotonin-antagonist, methysergide. Behav Neurosci. 2007 Jun;121(3):491-500.
- Exposure to enriched environment improves spatial learning performances and enhances cell density <strong
- >but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats.</strong>
- Dhanushkodi A, Bindu B, Raju TR, Kutty BM. Department of NeurophysiologyNational Institute of Mental Health and
- Neuro Sciences (NIMHANS Deemed University), Bangalore, India. The authors demonstrated the efficacy of enriched
- housing conditions in promoting the behavioral recovery and neuronal survival following subicular lesion in
- rats. Chemical lesioning of the ventral subiculum impaired the spatial learning performances in rats. The lesion
- also induced a significant degree of neurodegeneration in the CA1 and CA3 areas of the hippocampus and
- entorhinal cortex. Exposure to enriched housing conditions improved the behavioral performance and partially
- attenuated the neurodegeneration in the hippocampus. The choline acetyl transferase (ChAT) activity in the
- hippocampus remained unchanged following ventral subicular lesion and also following exposure to an enriched
- environment. The study implicates the effectiveness of activity-dependent neuronal plasticity induced by
- environmental enrichment in adulthood following brain insult. Copyright (c) 2007 APA, all rights reserved. Horm
- Behav. 2013 Jul 27. pii: S0018-506X(13)00139-6. Progesterone and vitamin D: Improvement after traumatic brain
- injury in middle-aged rats. Tang H, Hua F, Wang J, Sayeed I, Wang X, Chen Z, Yousuf S, Atif F, Stein DG.
- Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA. Progesterone (PROG) and vitamin D
- hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis,
- inflammation, oxidative stress, and<strong>excitotoxicity.</strong> We investigated whether 21days of VDH
- deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral
- and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral
- contusions of the medial frontal cortex. PROG (16mg/kg) and VDH (5μg/kg) were injected intraperitoneally 1h
- post-injury. Eight additional doses of PROG were injected subcutaneously over 7days post-injury. VDH deficiency
- itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes.
- Combination therapy showed moderate improvement in preserving spatial and reference memory but was not
- significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and
- the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing
- MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle,
- pathophysiological consequences of brain injury in older subjects. © 2013. KEYWORDS: Yang, glutamate stimulates
- DNA repair; methylation of dna during stress, hydrophobic Life Sci 1998;62(17-18):1717-21 Induction of
- inducible nitric oxide synthase and heme oxygenase-1 in rat glial cells. Kitamura Y, Matsuoka Y, Nomura Y,
- Taniguchi T Department of Neurobiology, Kyoto Pharmaceutical University, Japan. Recent observations
- suggest a possible interaction between the nitric oxide (NO)/NO synthases and carbon monoxide (CO)/heme
- oxygenases systems. We examined the effects of lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and NO
- donor such as S-nitroso-N-acetylpenicillamine (SNAP) on induction of inducible NO synthase (iNOS) and heme
- oxygenase-1 (HO-1) in mixed glial cells and in rat hippocampus. In in vitro glial cells, treatment with LPS
- induced the expression of 130-kDa iNOS after 6 h, and NO2- accumulation and enhancement of the protein level of
- 33-kDa HO-1 after 12 h. In addition, treatment with SNAP induced HO-1 expression after 6 h. Although a NOS
- inhibitor, such as N(G)-nitro-L-arginine (NNA), did not change LPS-induced iNOS expression, the inhibitor
- s<strong>uppressed both NO2- accumulation and the enhancement of HO-1.</strong> Immunocytochemistry showed
- that LPS-treatment induced iNOS-immunoreactivity predominantly in microglia, while this treatment induced
- HO-1-immunoreactivity in both microglia and astrocytes. These results suggest that endogenous NO production by
- iNOS in microglia causes autocrine- and paracrine-induction of HO-1 protein in microglia and astrocytes in rat
- brain.
-
- <p> </p>
- 4. Proc Soc Exp Biol Med. 1994 Oct;207(1):43-7. Dietary restriction modulates the norepinephrine content and
- uptake of the heart and cardiac synaptosomes. Kim SW, Yu BP, Sanderford M, Herlihy JT. Department of
- Physiology, University of Texas Health Science Center at San Antonio 78284. The present study was designed to
- examine the effects of long-term dietary restriction on cardiac sympathetic nerves and neurotransmitter. The
- food intake of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control rats fed ad
- libitum. The body and heart weights of rats diet restricted for 4.5 months were less than those of the ad
- libitum fed animals, while the heart weight to body weight ratios were higher<strong>. The norepinephrine (NE)
- content of hearts from</strong>
- <strong>restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38</strong>
- <strong>ng/g wet wt), although the total amoun</strong>t of NE per heart was unchanged. Similarly, the cardiac
- synaptosomal P2 fraction from restricted rats possessed a higher NE content (24.1 +/- 2.4 ng/mg protein) than
- the P2 fraction of ad libitum fed controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive
- norepinephrine uptake of the P2 fraction from restricted rats was significantly higher than that of control rats
- (9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg protein/hr). The NE uptakes of the two groups were similar when uptake was
- normalized to endogenous NE levels. These results demonstrate that long-term dietary restriction affects cardiac
- sympathetic nerve endings and suggest that part of the beneficial action of life-long dietary restriction on the
- age-related decline in cardiovascular regulation may be related to changes in cardiac sympathetic nerves. Int J
- Cancer. 1985 Apr 15;35(4):493-7. Muscarinic cholinergic receptors in pancreatic acinar carcinoma of rat. Taton
- G, Delhaye M, Swillens S, Morisset J, Larose L, Longnecker DS, Poirier GG. The active enantiomer of tritiated
- quinuclidinyl benzilate (3H(-)QNB) was used as a ligand to evaluate the muscarinic receptors. The 3H(-)QNB
- binding characteristics of muscarinic cholinergic receptors obtained from normal and neoplastic tissues were
- studied to determine changes in receptor properties during neoplastic transformation. Saturable and
- stereospecific binding sites for 3H(-)QNB are present in homogenates of rat pancreatic adenocarcinoma. The
- proportions of high- and low-affinity agonist binding sites are similar for neoplastic and normal tissues. The
- density of muscarinic receptors is higher in neoplastic (200 femtomoles/mg protein) than in normal pancreatic
- homogenates (80 femtomoles/mg protein). The muscarinic binding sites of the neoplastic and fetal
- pancreas show similar KD values which are higher than those observed for normal pancreas. 17: Cancer Res. 1986
- Nov;46(11):5706-14. Muscarinic receptor coupling to intracellular calcium release in rat pancreatic acinar
- carcinoma. Chien JL, Warren JR. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of
- cholinergic receptor protein affinity labeled with the muscarinic antagonist [3H]propylbenzilylcholine mustard
- revealed a major polypeptide with molecular weight of 80,000-83,000 in both acinar carcinoma and normal acinar
- cells of rat pancreas. Muscarinic receptor protein is therefore conserved in pancreatic acinar carcinoma. A
- small but significant difference was detected in the affinity of carcinoma cell receptors (Kd approximately 0.6
- nM) and normal cell receptors (Kd approximately 0.3 nM) for reversible binding of the muscarinic
- antagonist drug, N-methylscopolamine. In addition, carcinoma cell muscarinic receptors displayed homogeneous
- binding of the agonist drugs carbamylcholine (Kd approximately 31 microM) and oxotremorine (Kd approximately 4
- microM), whereas normal cell receptors demonstrated heterogeneous binding, with a minor receptor population
- showing high affinity binding for carbamylcholine (Kd approximately 3 microM) and oxotremorine (Kd approximately
- 160 nM), and a major population showing low affinity binding for carbamylcholine (Kd approximately 110 microM)
- and oxotremorine (Kd approximately 18 microM). Both carcinoma and normal cells exhibited concentration-dependent
- carbamylcholine-stimulated increases in cytosolic free Ca2+, as measured by 45Ca2+ outflux assay and
- intracellular quin 2 fluorescence. However, carcinoma cells were observed to be more sensitive to Ca2+
- mobilizing actions of submaximal carbamylcholine concentrations, demonstrating 50% maximal stimulation of
- intracellular Ca2+ release at a carbamylcholine concentration (approximately 0.4 microM) approximately one order
- of magnitude below that seen for normal cells. These results indicate altered muscarinic receptor coupling to
- intracellular Ca2+ release in acinar carcinoma cells, which manifests as a single activated receptor state
- for agonist binding, and increased sensitivity of Ca2+ release in response to muscarinic receptor stimulation.
- 1: Anticancer Drugs. 2008 Aug;19(7):655-71. Neurotransmission and cancer: implications for prevention and
- therapy. Schuller HM. Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary
- Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. <a
- href="mailto:hmsch@utk.edu"
- target="_blank"
- >hmsch@utk.edu</a>
- Published evidence compiled in this review supports the hypothesis that the development, progression, and
- responsiveness to prevention and therapy of the most common human cancers is strongly influenced, if not
- entirely orchestrated, by an imbalance in stimulatory and inhibitory neurotransmission. The neurotransmitters
- acetylcholine, adrenaline, and noradrenaline of the autonomic nervous system act as powerful upstream regulators
- that orchestrate numerous cell and tissue functions, by releasing growth factors, angiogenesis factors and
- metastasis factors, arachidonic acid, proinflammatory cytokines, and local neurotransmitters from cancer cells
- and their microenvironment. In addition, they modulate proliferation, apoptosis, angiogenesis, and metastasis of
- cancer directly by intracellular signaling downstream of neurotransmitter receptors. Nicotine and the
- tobacco-specific nitrosamines have the documented ability to hyperstimulate neurotransmission by both branches
- of the autonomic nervous system. The expression and function of these neurotransmitter pathways are cell type
- specific. Lifestyle, diet, diseases, stress, and pharmacological treatments modulate the expression and
- responsiveness of neurotransmitter pathways. Current preclinical testing systems fail to incorporate the
- modulating effects of neurotransmission on the responsiveness to anticancer agents and should be amended
- accordingly. The neurotransmitter gamma-aminobutyric acid has a strong inhibitory function on sympathicus-driven
- cancers whereas stimulators of cyclic adenosine monophosphate/protein kinase A signaling have strong inhibitory
- function on parasympathicus-driven cancers. Marker-guided restoration of the physiological balance in
- stimulatory and inhibitory neurotransmission represents a promising and hitherto neglected strategy for
- the prevention and therapy of neurotransmitter-responsive cancers. Psychological stress in IBD: new insights
- into pathogenic and ...
- <a href="http://www.ncbi.nlm.nih.gov/" target="_blank">www.ncbi.nlm.nih.gov</a> › Journal List › Gut ›
- v.54(10); Oct 2005 by JE Mawdsley - 2005 - Cited by 255 - Related articles Psychological stress has long been
- reported anecdotally to increase disease ..... atropine and was more marked in cholinesterase deficient
- Wistar-Kyoto rats. Neuropsychopharmacology. 2002 May;26(5):672-81. Sexual diergism of
- hypothalamo-pituitary-adrenal cortical responses to low-dose physotigmine in elderly vs. young women and men.
- Rubin RT, Rhodes ME, O'Toole S, Czambel RK. Center for Neurosciences Research, MCP Hahnemann University School
- of Medicine, Allegheny General Hospital, Pittsburgh, PA 15212, USA. <a
- href="mailto:rubin@wpahs.org"
- target="_blank"
- >rubin@wpahs.org</a>
- We previously demonstrated that the reversible cholinesterase inhibitor, physostigmine (PHYSO), administered to
- normal young adult women and men (average age 35 years) at a dose that produced few or no side effects, resulted
- in a sex difference (sexual diergism) in hypothalamo-pituitary-adrenal cortical (HPA) axis responses:
- Plasma <strong>ACTH(1-39), cortisol, and arginine vasopressin (AVP)</strong>
- <strong>concentrations increased to a significantly greater extent in the men than in</strong>
- <strong>the women. </strong>To explore the effect of age on these sexually diergic hormone responses, in
- the present study we used the same dose of PHYSO (8 microg/kg IV) to stimulate ACTH(1-39), cortisol, and AVP
- secretion in normal elderly, non-estrogen-replaced women and elderly men (average ages 73 years and 70 years,
- respectively). The subjects underwent three test sessions 5-7 days apart: PHYSO, saline control, and a second
- session of PHYSO. Serial blood samples were taken for hormone analyses before and after pharmacologic
- challenge.As with the previously studied younger subjects, PHYSO administration produced no side effects in
- about half the elderly subjects and mild side effects in the other half, with no significant female-male
- differences. <span><strong>The hormone responses were</strong></span>
- <span><strong>2-5 fold greater in the elderly subjects t</strong></span>han in the younger subjects, but in
- contrast to the younger subjects, the elderly men did not have significantly greater hormone responses to PHYSO
- administration than did the elderly women. The ACTH(1-39) and AVP responses to PHYSO for the two sessions were
- significantly positively correlated in the men (+0.96, +0.91) but not in the women. None of the hormone
- responses was significantly correlated with the presence or absence of side effects in either group of
- subjects.These results indicate<span><strong> a greater sensitivity of the HPA axis to low-dose PHYSO, and
- a loss of</strong></span>
- <span><strong>overall sex differences in hormone responses, in elderly compared with younger</strong></span>
- <span><strong>subjects. </strong></span>The lack of a difference in side effects between the elderly women
- and men and the lack of significant correlations between presence or absence of side effects and hormone
- responses suggest that the increase in hormone responses with aging is due to correspondingly increased
- responsiveness of central cholinergic systems and/or the HPA axis, and not to a nonspecific stress response.
- Horm Behav. 2013 Feb;63(2):284-90. Progesterone and neuroprotection. Singh M, Su C. Department of
- Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, Center FOR HER, University
- of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA. <a
- href="mailto:meharvan.singh@unthsc.edu"
- target="_blank"
- >meharvan.singh@unthsc.edu</a>
- Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as
- the experimental model. And while estrogen intervention in these animals has, at least partially, restored
- cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that
- the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone
- as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone
- as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline
- of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for
- diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of
- progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal
- models and in humans. <strong>Here, we review the evidence that supports the neuroprotective effects of
- progesterone and discuss the various mechanisms that are thought to mediate these protective
- effects.</strong> We also discuss the receptor pharmacology of progesterone's neuroprotective effects
- and present a conceptual model of progesterone action that supports the complementary effects of
- membrane-associated and classical intracellular progesterone receptors.<strong> In addition, we discuss
- fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin,
- medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined
- estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of
- progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain
- function.</strong>
-
- Brain Res. 2005 Jul 5;1049(1):112-9. <strong>Progesterone treatment inhibits the inflammatory agents that
- accompany traumatic brain injury.</strong> Pettus EH, Wright DW, Stein DG, Hoffman SW. Department of
- Cell Biology, Emory University, Atlanta, GA 30322, USA. Progesterone given after traumatic brain injury (TBI)
- has been shown to reduce the initial cytotoxic surge of inflammatory factors. We used Western blot techniques to
- analyze how progesterone might affect three inflammation-related factors common to TBI: complement factor C3
- (C3), glial fibrillary acidic protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after bilateral
- injury to the medial frontal cortex, adult male rats were given injections of progesterone (16 mg/kg) for 2
- days. Brains were harvested 48 h post-TBI, proteins were extracted from samples, each of which contained tissue
- from both the contused and peri-contused areas, then measured by Western blot densitometry. Complete C3, GFAP,
- and NFkappaB p65 were increased in all injured animals. However, in animals given progesterone post-TBI,<strong
- > NFkappaB p65 and the</strong>
- <strong>inflammatory metabolites of C3 (9 kDa and 75 kDa)</strong> were decreased in comparison to
- vehicle-treated animals. J Leukoc Biol 1996 Mar;59(3):442-50 Progesterone inhibits inducible nitric oxide
- synthase gene expression and nitric oxide production in murine macrophages. Miller L, Alley EW, Murphy WJ,
- Russell SW, Hunt JS Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas
- City, USA. The purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2)
- and progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO)
- by interferon-gamma(IFN-gamma)-and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment with P4 alone
- caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and
- mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently
- transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with
- IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW
- 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These
- observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within
- females and males that relates to macrophage-mediated host defense. J Reprod Immunol 1997 Nov
- 15;35(2):87-99 Female steroid hormones regulate production of pro-inflammatory molecules in uterine
- leukocytes. Hunt JS, Miller L, Roby KF, Huang J, Platt JS, DeBrot BL Department of Anatomy and Cell Biology,
- University of Kansas Medical Center, Kansas City 66160-7400, USA. <a
- href="mailto:jhunt@kumc.edu"
- target="_blank"
- >jhunt@kumc.edu</a> Estrogens and progesterone could be among the environmental signals that govern
- uterine immune cell synthesis of pro-inflammatory substances. In order to investigate this possibility, we first
- mapped expression of the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha)
- genes in the leukocytes of cycling and pregnant mouse uteri, then tested the ability of estradiol-17 beta (E2)
- and progesterone to influence gene expression. Immunohistochemistry, in situ hybridization, and other
- experimental approaches, revealed that the iNOS and TNF-alpha genes are expressed in mouse uterine mast cells,
- macrophages and natural killer cells (uNK). Gene expression in each cell type was noted to be dependent upon
- stage of the cycle or stage of gestation, implying potential relationships with levels of female hormones and
- state of cell differentiation or activation. Further in vivo and in vitro experiments showed that individual
- hormones have cell type-specific effects on synthesis of iNOS and TNF-alpha that are exerted at the level of
- transcription. In uterine mast cells, iNOS and TNF-alpha are promoted by E2 whereas preliminary studies in
- macrophages suggest that transcription and translation of the two genes are unaffected by E2 but are inhibited
- by progesterone. Hypothyroidism increases NO; T3, vs helpless; hypothyroid, escape deficit, Levine, et
- 1990.
- <strong>choline is increased in AD CSF Elble R;, Carriere;</strong>
-
- Genes Nutr. 2009 December; 4(4): 309–314.<strong> Dietary polyunsaturated fatty acids improve cholinergic
- transmission in the aged brain</strong> Willis LM, Shukitt-Hale B, Joseph JA. 28. Bloj B, Morero RD,
- Farias RN, Trucco RE (1973) Membrane lipid fatty acids and regulation of membrane-bound enzymes. Allosteric
- behaviour of erythrocyte Mg 2+-ATPase (Na++ K+)-ATPase and acetylcholinesterase from rats fed different
- fat-supplemented diets. Biochim Biophys Acta 311:67–79. [PubMed] 29. Vajreswari A, Narayanareddy K (1992) Effect
- of dietary fats on erythrocyte membrane lipid composition and membrane-bound enzyme activities. Metabolism
- 41:352–358. [PubMed] 30. Vajreswari A, Rupalatha M, Rao PS (2002) Effect of altered dietary n-6-to-n-3 fatty
- acid ratio on erythrocyte lipid composition and membrane-bound enzymes. J Nutr Sci Vitaminol 48:365–370.
- [PubMed] 31. Foot M, Cruz TF, Clandinin MT (1983) <strong>Effect of dietary lipid on synaptosomal
- acetylcholinesterase activity.</strong> Biochem J 211:507–509. [PMC free article] [PubMed] 33.
- Srinivasarao P, Narayanareddy K, Vajreswari A, Rupalatha M, Prakash PS, Rao P (1997) Influence of dietary fat on
- the activities of subcellular membrane-bound enzymes from different regions of the brain. Neuochem Int
- 31:789–794. [PubMed]
-
- <em>The protective effect of anticholinergic drugs, such as atropine or scopolamine, against various
- degenerative brain processes might lead a person to wonder whether the Berkeley enrichment experiments might
- not have been neurologically exactly the opposite of the stress experiments of Richter and Seligman, that
- is, reducing cholinergic processes with enrichment, increasing them with impoverishment of choices and
- experience. A drug, pilocarpine, </em>
-
- USING THE BRAIN FOR LIFE Living is development; the choices we make create our individuality. If genetically
- identical mice grow up in a large and varied environment, small differences in their experience will affect cell
- growth in their brains, leading to large differences in their exploratory behavior as they age (Freund, et al.,
- 2013). Geneticists used to say that "genes determine our limits," but this experiment shows that an environment
- can provide both limitations and opportunities for expanding the inherited potential. If our environment
- restricts our choices, our becoming human is thwarted, the way rats' potentials weren't discovered when they
- were kept in the standard little laboratory boxes. An opportunity to be complexly involved in a complex
- environment lets us become more of what we are, more humanly differentiated. A series of experiments that
- started at the University of California in 1960 found that rats that lived in larger spaces with various things
- to explore were better at learning and solving problems than rats that were raised in the standard little
- laboratory cages (Rosenzweig, 1960). Studying their brains, they found that the enzyme cholinesterase, which
- destroys the neurotransmitter, acetylcholine, was increased. They later found that the offspring of these rats
- were better learners than their parents, and their brains contained more cholinesterase. Their brains were also
- larger, with a considerable thickening of the cortex, which is considered to be the part mainly responsible for
- complex behavior, learning and intelligence. These processes aren't limited to childhood. For example,
- London taxi drivers who learn all the streets in the city develop a larger hippocampus, an area of the brain
- involved with memory. The 1960s research into environmental enrichment coincided with political changes in
- the US, but it went against the dominant scientific ideas of the time. Starting in 1945, the US government had
- begun a series of projects to develop techniques of behavior modification or mind control, using drugs,
- isolation, deprivation, and torture. In the 1950s, psychiatry often used lobotomies (about 80,000, before they
- were generally discontinued in the 1980s) and electroconvulsive "therapy," and university psychologists tortured
- animals, often as part of developing techniques for controlling behavior. The CIA officially phased out
- their MKultra program in 1967, but that was the year that Martin Seligman, at the University of Pennsylvania,
- popularized the idea of "learned helplessness." He found that when an animal was unable to escape from torture,
- even for a very short time, it would often fail to even try to escape the next time it was tortured.
- Seligman's lectures have been attended by psychologists who worked at Guantanamo, and he recently received a
- no-bid Pentagon grant of $31,000,000, to develop a program of "comprehensive soldier fitness," to train marines
- to avoid learned helplessness.
- <p> </p>
- Curt Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is
- shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally
- to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once
- (Richter, 1957). Rats which would normally be able to keep swimming in a tank for two or three days, would
- often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter made
- the important discovery that the hearts of the hopeless rats slowed down before they died, remaining relaxed and
- filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. The
- sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress,
- in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't
- previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been
- thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair.
- Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also
- secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has
- some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys
- acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow
- cells), maybe all cells, can secrete acetylcholine. Because cholinergic nerves have been opposed to the
- sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking
- at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation,
- however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or
- hypoglycemia. Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as
- chemicals that mimic them, such as the organophosphate insecticides, can impair the ability to think and learn.
- This suggested to some people that age-related dementia was the result of the deterioration of the cholinergic
- nerves in the brain. Drugs to increase the stimulating effects of acetylcholine in the brain (by inactivating
- cholinesterase) were promoted as treatment for Alzheimer's disease. Although herbal inhibitors were well
- known, profitable new drugs, starting with Tacrine, were put into use. It was soon evident that Tacrine was
- causing serious liver damage, but wasn't slowing the rate of mental deterioration. As the failure of the
- cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the similar memantine)
- was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was proposed a few times
- for treating dementia, and amantadine, which was also considered anticholinergic, was proposed for some
- mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have seemed odd to
- propose that an anticholinergic drug be used to treat a condition that was being so profitably treated with a
- pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker," to protect the
- remaining cholinergic nerves, so that both drugs could be prescribed simultaneously. The added drug seems to
- have a small beneficial effect, but there has been no suggestion that this could be the result of its
- previously-known anticholinergic effects. Over the years, some people have suspected that Alzheimer's disease
- might be caused partly by a lack of purpose and stimulation in their life, and have found that meaningful,
- interesting activity could improve their mental functioning. Because the idea of a "genetically determined
- hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy for all
- kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the association of
- increasing cholinesterase activity with improving brain function should be of interest. The after-effect of
- poisoning by nerve gas or insecticide has been compared to the dementia of old age. The anticholinergic drugs
- are generally recognized for protecting against those toxins. Traumatic brain injury, even with improvement in
- the short term, often starts a long-term degenerative process, greatly increasing the likelihood of dementia at
- a later age. A cholinergic excitotoxic process is known to be involved in the traumatic degeneration of nerves
- (Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been recommended for many years to treat
- traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al., 1986). In 1976 there was an experiment
- (Rosellini, et al.) that made an important link between the enrichment experiments and the learned helplessness
- experiments. The control animals in the enrichment experiments were singly housed, while the others shared a
- larger enclosure. In the later experiment, it was found that the rats "who were reared in isolation died
- suddenly when placed in a stressful swimming situation," while the group-housed animals were resistant,
- effective swimmers. Enrichment and deprivation have very clear biological meaning, and one is the negation of
- the other. The increase of acetylcholinesterase, the enzyme that destroys acetylcholine, during
- enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by increasing the activity
- of the cholinergic system, we should expect that a cholinergic drug might substitute for inescapable stress, as
- a cause of learned helplessness, and that an anticholinergic drug could cure learned helplessness. Those tests
- have been done: "Treatment with the anticholinesterase, physostigmine, successfully mimicked the effects of
- inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide antagonized the effects of
- physostigmine, and when administered prior to escape testing antagonized the disruptive effects of previously
- administered inescapable shock." (Anisman, et al., 1981.) This kind of experiment would suggest that the
- anticholinesterase drugs still being used for Alzheimer's disease treatment aren't biologically helpful. In an
- earlier newsletter I discussed the changes of growth hormone, and its antagonist somatostatin, in association
- with dementia: Growth hormone increases, somatostatin decreases. The cholinergic nerves are a major factor in
- shifting those hormones in the direction of dementia, and the anticholinergic drugs tend to increase the ratio
- of somatostatin to growth hormone. Somatostatin and cholinesterase have been found to co-exist in single nerve
- cells (Delfs, et al., 1984). Estrogen, which was promoted so intensively as prevention or treatment for
- Alzheimer's disease, was finally shown to contribute to its development. One of the characteristic effects of
- estrogen is to increase the level of growth hormone in the blood. This is just one of many ways that estrogen is
- associated with cholinergic activation. During pregnancy, it's important for the uterus not to contract.
- Cholinergic stimulation causes it to contract; too much estrogen activates that system, and causes miscarriage
- if it's excessive. An important function of progesterone is to keep the uterus relaxed during pregnancy. In the
- uterus, and in many other systems, progesterone increases the activity of cholinesterase, removing the
- acetylcholine which, under the influence of estrogen, would cause the uterus to contract. Progesterone is being
- used to treat brain injuries, very successfully. It protects against inflammation, and in an early study,
- compared to placebo, lowered mortality by more than half. It's instructive to consider its anticholinergic role
- in the uterus, in relation to its brain protective effects. When the brain is poisoned by an organophosphate
- insecticide, which lowers the activity of cholinesterase, seizures are likely to occur, and treatment with
- progesterone can prevent those seizures, reversing the inhibition of the enzyme (and increasing the activity of
- cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar effects of progesterone on
- cholinesterase occur in women (Fairbrother, et al., 1989), implying that this is a general function of
- progesterone, not just something to protect pregnancy. Estrogen, with similar generality, decreases the activity
- of cholinesterase. DHEA, like progesterone, increases the activity of cholinesterase, and is brain protective
- (Aly, et al., 2011). Brain trauma consistently leads to decreased activity of this enzyme (Östberg, et al.,
- 2011; Donat, et al., 2007), causing the acetylcholine produced in the brain to accumulate, with many interesting
- consequences. In 1997, a group (Pike, et al.) created brain injuries in rats to test the idea that a
- cholinesterase inhibitor would improve their recovery and ability to move through a maze. They found instead
- that it reduced the cognitive ability of both the injured and normal rats. An anticholinergic drug, selegeline
- (deprenyl) that is used to treat Parkinson's disease and, informally, as a mood altering antiaging drug, was
- found by a different group (Zhu, et al., 2000) to improve cognitive recovery from brain injuries. One of
- acetylcholine's important functions, in the brain as elsewhere, is the relaxation of blood vessels, and this is
- done by activating the synthesis of NO, nitric oxide. (Without NO, acetylcholine constricts blood vessels;
- Librizzi, et al., 2000.) The basic control of blood flow in the brain is the result of the relaxation of the
- wall of blood vessels in the presence of carbon dioxide, which is produced in proportion to the rate at which
- oxygen and glucose are being metabolically combined by active cells. In the inability of cells to produce CO2 at
- a normal rate, nitric oxide synthesis in blood vessels can cause them to dilate. The mechanism of relaxation by
- NO is very different, however, involving the inhibition of mitochondrial energy production (Barron, et al.,
- 2001). Situations that favor the production and retention of a larger amount of carbon dioxide in the tissues
- are likely to reduce the basic "tone" of the parasympathetic nervous system, as there is less need for
- additional vasodilation. Nitric oxide can diffuse away from the blood vessels, affecting the energy metabolism
- of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from nitric oxide (Chen, et
- al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed from the intestine
- (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide themselves. Nitric
- oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011). Nitric oxide activates
- processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production of nitric oxide
- protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh, 2013). Brain trauma
- causes a large increase in nitric oxide formation, and blocking its synthesis improves recovery (Hüttemann, et
- al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and the protective
- anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997). Stress, including
- fear (Campos, et al., 2013) and isolation (Zlatković and Filipović, 2013) can activate the formation of nitric
- oxide, and various mediators of inflammation also activate it. The nitric oxide in a person's exhaled breath can
- be used to diagnose some diseases, and it probably also reflects the level of their emotional well-being. The
- increase of cholinesterase by enriched living serves to protect tissues against an accumulation of
- acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy production, and
- to activate autolytic or catabolic processes, which are probably involved in the development of a thinner
- cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue renewal
- processes are able to predominate in the enriched animals. Environmental conditions that are favorable for
- respiratory energy production are protective against learned helplessness and neurodegeneration, and other
- biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the
- formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat
- neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010).
- Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990). During the
- development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal
- of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the
- animal inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been
- created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988). Hypothyroidism and excess
- cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar
- symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by
- increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).
- Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease
- (Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and
- degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners,
- which can be contaminated with organophosphate fumes coming from the engine used to compress it. Possibly
- the most toxic component of our environment is the way the society has been designed, to eliminate meaningful
- choices for most people. In the experiment of Freund, <em>et al.</em>, some mice became more exploratory
- because of the choices they made, while others' lives became more routinized and limited. Our culture reinforces
- routinized living. In the absence of opportunities to vary the way you work and live to accord with new
- knowledge that you gain, the nutritional, hormonal and physical factors have special importance. Supplements of
- thyroid and progesterone are proven to be generally protective against the cholinergic threats, but there are
- many other factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits
- the production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et
- al., 2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et
- al., 2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without
- excess ultraviolet, should be available every day. The cholinergic system is much more than a part of the
- nervous system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing
- intake of phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009),
- and from choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are
- intended to increase the effects of nitric oxide and acetylcholine should be avoided. © Ray Peat Ph.D. 2016. All
- Rights Reserved. www.RayPeat.com
- </body>
- </html>
|
