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    <head><title>Epilepsy and Progesterone</title></head>
    <body>
        <h1>
            Epilepsy and Progesterone
        </h1>
        <p>
            The length of the life-span, and of the period of youth or immaturity, is closely associated with the size
            of the brain, and the brain has a very high rate of metabolism. When something interferes with this very
            high metabolic rate, the consequences may be instantanteous,* or developmental, or chronic and degenerative,
            or even transgenerational. The issue of epilepsy centers on questions of brain metabolism, and so it has all
            of those dimensions.
        </p>
        <p>
            As I discuss the mechanisms known to predispose a person to epilepsy, I will emphasize the centrality of
            oxidative energy production, and show how "stroke," "stress," "hyperactivity," "dementia," and other brain
            syndromes are related to "epilepsy." (Similar processes are being studied in the heart and other tissues;
            eventually, we might have a general language that will make it easier to understand the parallels in the
            various kinds of "seizure" in any organ.)
        </p>
        <p>
            As an old term, "epilepsy" has aquired a burden of pseudoscientific ideas, covering old superstitions with
            an overlay of new superstitions. [Hereditary epilepsy has been discussed in countless textbooks and medical
            journals, but I think a much better case could be made for the inheritance of a tendency to offer stupid
            genetic explanations.] "Hereditary epilepsy" and "idiopathic epilepsy" are seriously pathogenic terms;
            "brain scar" sometimes has a factual basis, but most often the term is an evasion of understanding.
        </p>

        <p>
            As long as we realize that the essential meaning of the word is "something that grabs you," "epilepsy" is a
            convenient way to refer to a cluster of convulsive states, fainting spells, night-terrors and nightmares,
            and strange sensations.
        </p>
        <p>
            Seizures can be caused by lack of glucose, lack of oxygen, vitamin B6 deficiency, and magnesium deficiency.
            They are more likely to occur during the night, during puberty, premenstrually, during pregnancy, during the
            first year of life, and can be triggered by hyperventilation, running, strong emotions, or unusual sensory
            stimulation. Water retention and low sodium increase susceptibility to seizures. When I was in high school,
            our dog found and ate a pint of bacon grease, and shortly afterward had a convulsive seizure. I knew of
            veterinarians who treated seizures in dogs with a vermifuge, so it seemed obvious that a metabolic
            disturbance, especially if combined with intestinal irritation, could cause fits.
        </p>
        <p>
            It was undoubtedly such observations that led some physicians to advocate removal of the colon as treatment
            for epilepsy. Pregnancy and the menstrual cycle have been recognized as having something to do with
            seizures, but when seizures occurred only during pregnancy, they were classified as nonepileptic, and when
            they had a clear premenstrual occurrence, they were likely to be classified as "hysterical fits," to be
            treated with punishment.
        </p>
        <p>
            It has been observed that all "recognized" anti-seizure drugs are teratogenic, and women who are taking such
            drugs are told that pregnancy might kill them if they stop the drug, but that their babies will have a
            greatly increased risk of birth defects if they take the drugs during pregnancy. This is why a better
            understanding of epilepsy is very important. Old therapies are mainly important for the insight they can
            give into the nature of the physiological problem. Some of the well established clinical-laboratory
            observations (F. Mora, and C. S. Babel, for example) give strong hints as to the physiological problem, for
            example, low albumin, high prealbumin, low magnesium and high calcium all suggest hypothyroidism. (Problems
            with the bowel, liver, and sex hormones are highly associated with hypothyroidism, both as causes and as
            effects.) Water retention was so clearly involved in seizures that increased water intake was used as a
            diagnostic procedure. (R. Grinker) Unfortunately, animal experiments showed that water intoxication
            increased susceptibility to seizures even in normal individuals. Low sodium content in the body fluids also
            predisposed to seizures, so that someone with hyponatremia (low blood sodium) would be more susceptible to
            induction of a seizure by excessive water intake. (Excessive water uptake is still recognized as a factor in
            seizures, but now it is seen as part of a complex process, involving energy, hormones, and transmitter
            substances. E.g., Kempski; Chan.)
        </p>
        <p>
            Hypothyroid people tend to lose sodium easily, and unopposed estrogen increases water retention, without an
            equivalent sodium retention, so low thyroid, high estrogen people have two of the conditions (edema and
            hyponatremia) known to predispose to seizures. Another outstanding feature of seizures of various sorts is
            that they are most likely to occur at night, especially in the early pre-dawn hours. Low blood sugar and
            high adrenalin predominate during those hours. Hypoglycemia, in itself, like oxygen deprivation, is enough
            to cause convulsions.
        </p>
        <p>
            Progesterone and thyroid promote normal energy production, and their deficiency causes a tendency toward
            hypoglycemia, edema and instability of nerves.
        </p>
        <p>
            Twenty years ago, a woman who was considered demented visited me. From the age of 21, she had been
            increasingly disabled by premenstrual migraines. When she was 35 she was a school teacher, and during the
            summer a neurologist told her that dilantin would help her headaches, because "migraine is similar to
            epilepsy." Although she told the neurologist that the drug made her "too stupid to teach school," he offered
            her no alternatives, and didn't mention that sudden withdrawal from the drug could trigger a seizure. When
            classes started she discontinued the dilantin and had a seizure. The neurologist said the seizure proved
            that migraines were a form of epilepsy. At the age of 52, she spent about 20 hours a day in bed, and
            couldn't go outside by herself, because she would get lost. After using a little progesterone for a few
            days, she stopped having seizures, discontinued her drugs, and was able to work. When she returned to
            graduate school, she got straight As, and earned her masters' degree in gerontology. But she had lost 17
            years because the drug industry had covered up the role of the hormones in epilepsy, migraine, and the
            perimenstrual syndrome.
        </p>

        <p>
            The most popular anticonvulsant drugs are both neurotoxic and teratogenic, that is, they damage the
            patient's brain, and greatly increase the incidence of birth defects. The Nazis justified their horrible
            medical experiments as "science," but the effects of epilepsy medicine in the last half century have been
            similar in effect, grander in scale, and without any scientific justification.
        </p>
        <p>
            Besides the specific promotional efforts of the drug industry and their branch of government, there is a
            broader situation that makes their work easier. It is a culture of goony ideas, that ultimately emanates
            from the academic elite, which (since Descartes, and before) places "thought" above evidence. In biology,
            "genes" and "membranes" are confused ideas that are used to justify actions that aren't based on evidence.
            For the Nazis, "cultural degeneracy" was a medical-biological-political category based on that style of
            thinking. In the United States, "genes" for epilepsy, hyperactivity, language development, IQ, eclampsia,
            etc., are "found" at Harvard/MIT/Stan- ford/Yale/Univ. of California, etc., by an elite whose wits have been
            dulled by environmental deprivation, that is, by a lack of criticism.
        </p>
        <p>
            By manipulating the diet and environment, animals can be made more or less seizure-prone, and it happens
            that the changes that affect the brain affect all other organs, in ways that are now fairly well understood.
            Examining the cellular events associated with a seizure is useful for therapy and prevention of seizures,
            but the same methods are helpful for many other conditions. It is now clearly established that stress can
            cause brain damage, as well as other diseases. Now that our public health establishment has eliminated
            smoking from public places, maybe they can find a way to reduce stress and disease by removing morons from
            positions of power.
        </p>
        <p>
            Excitotoxicity, in its simplest sense, is the harmful cellular effect (death or injury) caused by an
            excitatory transmitter such as glutamate or aspartate acting on a cell whose energetic reserves aren't
            adequate to sustain the level of activity provoked by the transmitter. Once an excitotoxic state exists, the
            consequences of cell exhaustion can increase the likelihood that the condition will spread to other cells,
            since any excitation can trigger a complex of other excitatory processes. As calcium enters cells, potassium
            leaves, and enzymes are activated, producing free fatty acids (linoleic and arachidonic, for example) and
            prostaglandins, which activate other processes, including lipid peroxidation and free radical production.
            Protein kinase C (promoted by unsaturated fats and estrogen) facilitates the release of excitatory amino
            acids. (See J. W. Phillis and M. H. O'Regan, "Mechanisms of glutamate and aspartate release in the ischemic
            rat cerebral cortex," Br. Res. 730(1-2), 150-164, 1996.) Estrogen supports acetylcholine release, which
            leads to increased extracellular potassium and excitatory amino acids. (See R. B. Gibbs, et al., "Effects of
            estrogen on potassium-stimulated acetylcholine release in the hippocampus and overlying cortex of adult
            rats," Br. Res. 749(1), 143-146, 1997.)
        </p>

        <p>
            Estrogen also stimulates the production of free radicals. Calcium, free radicals, and unsaturated free fatty
            acids impair energy production, decreasing the ability to regulate potassium and calcium. The increased
            estrogen associated with seizures is associated with reduced serum calcium (Jacono and Robertson, 1987).
            Feedback self-stimulation of free radicals, free fatty acids, and prostaglandins create a bias toward
            increased excitation.
        </p>
        <p>
            Ammonia is produced by stimulated nerves, and normally its elimination helps to eliminate and control the
            excitotoxic amino acids, glutamate and aspartate. The production of urea consumes aspartic acid, converting
            it to fumaric acid, but this requires carbon dioxide, produced by normal mitochondrial function. A
            deficiency of carbon dioxide would reduce the delivery of oxygen to the brain by constricting blood vessels
            and changing hemoglobin's affinity for oxygen (limiting carbon dioxide production), and the failure to
            consume aspartate (in urea synthesis) and glutamate (as alpha-ketoglutarate) and aspartate (as oxaloacetate)
            in the Krebs cycle, means that as energy becomes deficient, excitation tends to be promoted. This helps to
            explain the fact that seizures can be induced by hypoxia. (Balloonists and mountain climbers at extremely
            high elevations have mentioned suffering from severe insomnia. The mechanisms of excitotoxicity are probably
            involved in other forms of insomnia, too.) Antioxidants help to control seizures, by reducing the excitatory
            contribution of free radicals and lipid peroxidation. Since excitation can promote the toxic forms of
            oxidation, many surprising substances turn out to have an "antioxidant" function. Magnesium, sodium
            (balancing calcium and potassium), thyroid and progesterone (increasing energy production), and in some
            situations, carbon dioxide. Aspirin, by inhibiting prostaglandin synthesis (and maybe other mechanisms)
            often lowers free radical production. Adenosine seems to have a variety of antioxidant functions, and one
            mechanism seems to be its function as an antiexcitatory transmitter. One of estrogen's excitant actions on
            the brain probably involves its antagonism to adenosine (Phillis and O'Regan, 1988).
        </p>
        <p>
            Albumin, besides maintaining blood volume and preventing edema, serves to protect respiration, by binding
            free fatty acids. Estrogen blocks the liver's ability to produce albumin, and increases the level of
            circulating free fatty acids. Free fatty acids cause brain edema. This is probably another aspect of
            estrogen's contribution to seizure susceptibility. Magnesium sulfate has been used for generations in India
            to treat eclampsia and "toxemia" of pregnancy, and its effectiveness is gradually coming to be recognized in
            the U.S. Increasingly, magnesium deficiency is recognized as a factor that increases susceptibility to
            seizures. (Valenzuela and Benardo, 1995; Slandley, et al., 1995). Hypothyroidism reduces the ability of
            cells to retain magnesium. Thyroid does many things to protect against seizures. It keeps estrogen and
            adrenal hormones low, and increases production of progesterone and pregnenolone. It facilitates retention of
            magnesium and of sodium, and prevents edema in a variety of ways.
        </p>

        <p>
            Progesterone, because of its normal anesthetic function (which prevents the pain of childbirth when its
            level is adequate), directly quiets nerves, and in this way suppresses many of the excitotoxic processes. It
            has direct effects on mitochondria, promoting energy production, and it facilitates thyroid hormone
            functions in various ways. It promotes the elimination of estrogen from tissues, and is a "diuretic" in
            several benign ways, that are compatible with maintenance of blood volume. It antagonizes the
            mineralocorticoids and the glucocorticoids, both of which promote seizures. (Roberts and Keith, 1995.) The
            combination of hypoglycemia with elevation of cortisone probably accounts for the nocturnal incidence of
            seizures.
        </p>
        <p>
            If progesterone's antiepileptic effectiveness were not enough (and it is very effective even in irrational
            pharmaceutical formulations), the fact that it reduces birth defects, and promotes brain development and
            nerve repair should assure its general use in women with a history of seizures, until it is established that
            they are no longer "epileptic." Although thyroid, progesterone, and a high quality protein diet will
            generally correct the epilepsy problem, it is important to mention that the involvement of unsaturated fats
            and free radicals in seizure physiology implies that we should minimize our consumption of the unsaturated
            fats. Even years after eliminating them from the diet, their release from tissue storage can prolong the
            problem, and during that time the use of vitamin E is likely to reduce the intensity and frequency of
            seizures. Coconut oil lowers the requirement for vitamin E, and reduces the toxicity of the unsaturated fats
            (see Cleland, et al.), favoring effective respiration and improving thyroid and progesterone production.
            Endotoxin formed in the bowel can block respiration and cause hormone imbalances contributing to instability
            of the nerves, so it is helpful to optimize bowel flora, for example with a carrot salad; a dressing of
            vinegar, coconut oil and olive oil, carried into the intestine by the carrot fiber, suppresses bacterial
            growth while stimulating healing of the wall of the intestine. The carrot salad improves the ratio of
            progesterone to estrogen and cortisol, and so is as appropriate for epilepsy as for premenstrual syndrome,
            insomnia, or arthritis.
        </p>
        <p>NOTES:</p>

        <p>
            When the brain loses its oxygen supply, consciousness is lost immediately, before there is much decrease in
            the ATP concentration. This has led to the proposal of interesting "electronic" ideas of consciousness, but
            there is another way of viewing this. While ATP constitutes a kind of reservoir of cellular energy, the flow
            of carbon dioxide through the brain cell is almost the mirror image of the flow of oxygen. Oxygen scarcity
            leads directly to carbon dioxide scarcity. The "sensitive state," consciousness, might require the presence
            of carbon dioxide as well as ATP, to sustain a cooperative, semi-stable, state of the cytoplasmic proteins.
            The ability of ordinary light to trigger a conformation change in the hemoglobin-carbon monoxide-carbon
            dioxide system shows how sensitive a system with only a few elements can be. At the other extreme from
            consciousness, there is the evidence that carbon dioxide is essential for even the growing/living state of
            protozoa, algae, and bacteria.(O. Rahn, 1941.)
        </p>
        <p>
            O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "On page 113 of this volume,
            the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown to apply
            to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and under
            these circumstances, bacteria cannot multiply."
        </p>
        <p><h3>REFERENCES</h3></p>

        <p>
            E. Tauboll, et al., "The progesterone metabolite 5-alpha-pregnan-3-alpha-ol-20-one reduces K+-induced GABA
            and glutamate release from identified nerve terminals in rat hippocampus--a semiquantitative
            immunocytochemical study," Brain Research 623(2), 329-333, 1993.
        </p>
        <p>
            E. Tauboll and S. Lindstrom, similar article in Epilepsy Research 14(1), 17-30, 1993.
        </p>
        <p>
            G. K. Herkes, et al., "Patterns of seizure occurrence in catamenial epilepsy," Epilepsy Research 15(1),
            47-52, 1993. (Seizures are more frequent at ovulation, during the two days before menstruation, and during
            menstruation.)
        </p>
        <p>
            M. S. Myslobodsky, "Proconvulsant and anticonvulsant effects of stress--the role of neuroactive steroids,"
            Neuroscience &amp; Biobehavioral Reviews 17(2_, 129-139, 1993. (Discusses steroid-induced sedation,
            excitatory steroids, stress and epilepsy, GABA and respiratory functions, and asymmetric brain injury.)
        </p>

        <p>
            P. Berbel, et al., "Organization of auditory callosal connections in hypothyroid adult rats," European J. of
            Neuroscience 5(11), 1465-1478, 1993.(Changes in cortical connectivity related to epilepsy associated with
            early hypothyroidism.)
        </p>
        <p>
            D. A. Marks and B. L. Ehrenberg, "Migraine-related seizures in adults with epilepsy, with EEG correlation,"
            Neurology 43(12), 2475-2483, 1993. ("Patients with catamenial epilepsy and patients with migraine with aura
            were at an increased risk for an association between..." migraine and epilepsy.)
        </p>
        <p>
            R. D. Brinton, "The neurosteroid 3-alpha-hydroxy-5-alpha-pregnan-20-one induces cytoarchitectural regression
            in cultured fetal hippocampal neurons," J. of Neuroscience 145(5 part 1), 2763-2774, 1994. J. W. Phillis and
            M. H. O'Regan, "Effects of estradiol on certain cortical neurons and their responses to adenosine," Br. Res.
            Bull. 20(2), 151-155, 1988.
        </p>
        <p>
            J. O. McNamara, "Human hypoxia and seizures: Effects and interactions," Advances in Neurology 26, S. Fahn,
            et al., eds., Raven Press, N.Y., 1979. (Seizures can cause hypoxia, etc.)
        </p>
        <p>
            M. R. Liebowitz, et al., "Lactate provocation of panic attacks: 2. Biochemical and physiological findings."
            Arch. Gen. Psychiatry 42(7), 709-719, 1985. "Before receiving lactate, patients showed higher heart rates
            than controls and also signs of hyperventilation." R. H. Mattson, et al., "Treatment of seizures with
            medroxyprogesterone acetate: Preliminary report," Neurology 34, 1255-7, 1984. M. W. Newmark, et al,
            "Catamenial epilepsy: A review," Epilepsia 21, 281-300, 1980.
        </p>

        <p>
            J. W. Phillis and M. H. O'Regan, "Effects of estradiol on cerebral cortex neurons and their responses to
            adenosine," Br. Res. Bull. 20(2), 151-155, 1966. (Antagonism to endogenous adenosine may account for the
            excitant actions of estradiol in the brain.)
        </p>
        <p>
            J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effects of adenosine
            agonists," Br. Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxicity, could contribute to
            ischemic brain injury.)
        </p>
        <p>
            T. Backstrom, "Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual
            cycle," Acta Neurol. Scand. 54, 321-347, 1976. (Seizures are more frequent at menstruation and ovulation.)
            T. Backstrom, et al., "Effects of intravenous progesterone infusion on the epilepsy discharge frequency in
            women with partial epilepsy," Acta Naurol. Scan. 69(4), 240-248, 1984.
        </p>

        <p>
            A. W. Zimmerman, "Hormones and epilepsy," Neurol. Clin. 4(4), 853-861, 1985. "Progesterone appears to be
            especially effective in treating seizures." J. Bauer, et al., "Catamenial seizures--an analysis," Nervenarzt
            66(10), 760-769, 1995. "...when anticonvulsants have failed to suppress seizures, progesterone or
            progesterone-derivates have been administered with success." R. H. Mattson, et al., "Seizure frequency and
            the menstrual cycle: a clinical study," Epilepsia 22, 242, 1981. J. Logothetis, et al., "The role of
            estrogens in catamenial exacerbation of epilepsy," Neurology (Minneap) 9, 352-360, 1959. J Laidlaw,
            "Catamenial epilepsy," Lancet 2, 1235-7, 1956. S. Landgren and O. Selstam, "Interaction between
            17-beta-oestradiol and 3alpha-hydroxy-5alpha pregnane- 20-one in the control of neuronal excitability in
            slices from the hippocampus in vitro of guinea-pigs and rats," Acta Physiologica Scandinavica 154(2),
            165-176, 1995. C. A. Frye, "The neurosteroid 3 alpha, 5 alpha-THP has antiseizure and possible
            neuroprotective effects in an animal model of epilepsy," Brain Research 696(1-2), 113-120, 1995.
        </p>
        <p>
            G. K. Herkes, "Drug treatment of catamenial epilepsy," CNS Drugs 3(4), 260-266, 1995. (Mentions use of
            diuretics, progesterone, and the very high incidence of premenstrucal seizure, and of abnormal menstrual
            cycles in women with epilepsy.)
        </p>
        <p>
            E. Spiegel and H. Wycis, "Anticonvulsant effects of steroids," J. Lab. Clin. Med. 33, 945-957, 1947.
        </p>

        <p>
            G. Holmes, "Anticonvulsant effect of hormones on seizures in animals," 265-268, in: R. Porter, R. H.
            Mattson, A. Ward, and M. Dam, eds., Advances in Epileptology, 15th Epilepsy International Symposium, New
            York, Raven Press, 1984.
        </p>
        <p>
            H. W. Zimmerman, et al., "Medroxyprogesterone acetate in the treatment of seizures associated with
            menstruation," J. Pediatr. 83, 959-963, 1973. R. H. Mattson, et al., "Medroxy-progesterone treatment of
            women with uncontrolled seizures," Epilepsia 22, 242, 1981. A. Rosenfield, et al., "The Food and Drug
            Administration and medroxyprogesterone acetate: What are the issues?" JAMA 249, 2922-2928. 1983. V.
            Valenzuela and L. S. Benardo, "An in vitro model of persistent epileptiform activity in neocortex," Epilepsy
            Research 21(3), 195-204, 1995. C. A. Slandley, et al., "Magnesium sulfate reduces seizures induced by
            central administration of the excitatory amino acid N-methyl-D-aspartate in rats," Hypertension in Pregnancy
            14(2), 235-244, 1995. ("Magnesium is a physiological blocker of the NMDA receptor.") M. Simonale, et al.,
            "Adenosine JA(1) receptors in the rat brain in the kindled model of epilepsy," Eur. J. of Pharmac. 265(3),
            121-124, 1994. (Adenosine has potent anticonvulsive effects in various seizure models.) P. S. Timiras and H.
            F. Hill, Chapter 43, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser, et al, Raven Press,
            N.Y., 1980. (Estrogens increase cortical excitability, lower convulsive thresholds, and are clearly
            associated with certain cases of petit mal epilepsy. "The mechanisms of this so-called 'catamenial' epilepsy
            are unknown. Water retention and electrolyte changes in the brain...have been implicated..."
            "...acetazolamide (diamox), a carbonic anhydrase inhibitor and diuretic, is successful in the treatment of
            many cases of these seizures, and in refractory cases progestational agents are effective." "...seizures
            were more severe and frequent during the estrogen-dominated preovulatory phase of the menstrual cycle than
            in the progesterone-dominated postovulatory phase." "...ACTH may trigger epileptic convulsions by increasing
            intracellular sodium concentration throughout the body." "Progesterone can effectively reduce the frequency
            and severity of intractable seizures associated with menstruation..." "Considering the markedly
            proconvulsant effects of estrogens, it is surprising that the differential effects of sex hormones on
            central neurotransmitter mechanisms have been only sparingly investigated." "...estradiol decreases
            monoamine oxidase activity and increases choline acetyltransferase activity in various brain regions."
            "...hypothyroidism in perinatal animals has striking suppressant effects on GABA metabolism and also causes
            a persistent lowering of electroconvulsive threshold.")
        </p>

        <p>
            P. S. Timiras and H. F. Hill, "Antiepileptic drugs," Chapter 43; E. Roberts, "Epilepsy and antiepileptic
            drugs: A speculative synthesis," Chapter 44, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H.
            Glaser, et al., Raven Press, New York, 1980. E. V. Nikushkin, et al.,"Relationship between peroxidation and
            phospholipase hydrolysis of lipids in synaptosomes," B.E.B.M.107(2)183-186, 1989. Free unsaturated fatty
            acids are liberated in nerve endings and contribute to lipid peroxidation in epileptic seizures. P. A. Long,
            et al., "Importance of abnormal glucose tolerance (hypoglycemia and hyperglycemia) in the aetiology of
            pre-eclampsia," Lancet 1, 923-925, 1977.
        </p>
        <p>
            M. M. Singh, "Carbohydrate metabolism in pre-eclampsia," Br. J. Obstet. Gynaecol. 83, 124-131, 1976.
        </p>

        <p>
            N. A. Ziboh, et al., Prostaglandins 5, 233, 1974. (Eicosatrienoic (20:3 n-9) acid is a potent inhibitor of
            prostaglandin synthetase.) C. Galli and C. Spagnuolo, "The release of brain free fatty acids during
            ischaemia in essential fatty acid-deficient rats," J. of Neurochemistry 26, 401-404, 1976.
        </p>
        <p>
            B. Meldrum, "Excitatory amino acids and anoxic-ischemic brain damage," Trends Neurosci. 8, 47-48, 1985.
        </p>
        <p>
            B. Halliwell, "Oxidants and human disease: Some new concepts," FASEB J. 1, 358-364, 1987. "...injury to the
            brain causes release of metal ions that stimulate lipid peroxidation." "..lipid peroxidation...could be
            important in spreading injury to adjacent cells...." P.H. Chan, et al., "Effects of excitatory
            neurotransmitter amino acids on swelling of rat brain cortical slices," J. Neurochem. 33, 1309, 1979. P. H.
            Chan and R. A. Fishman, "Alterations of membrane integrity and cellular constituents by arachidonic acid in
            neuroblastoma and glioma cells," Brain Res. 248, 151, 1982.
        </p>
        <p>
            T. O. Kokate, et al., "Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic
            seizures and status epilepticus in mice," Neuropharmacology 35(8), 1049-1056, 1996. (With a second dose,
            "complete protection from the...limbic seizures and status epilepticus was obtained.") J. W. Phillis, et
            al., "Effect of adenosine receptor agonist on spontaneous and K+-evoked acetylcholine release from the in
            vivo rat cerebral cortex," Brain Res. 605(2), 293-297, 1993.
        </p>
        <p>
            J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effectss of adenosine
            agonists," Brain Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxic depolarization,
            intracellular calcium levels, and neural degeneration, and could contribute to ischemic brain injury.
        </p>

        <p>
            R. L. Grief, "Thyroid status influences calcium ion accumulation and retention by rat liver mitochondria,"
            Proc. Soc. Exp. Biol. &amp; Med. 189(1), 39-44, 1988.
        </p>
        <p>
            L. G. Cleland, et al., "Effects of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma
            lipid fractions and tissue plasma lipids," Lipids 31(8), 829-837, 1996. "Dietary enrichment with ETrA
            warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity,
            as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis
            adversely." A. A. Starkov, et al., "Regulation of the energy coupling in mitochondria by some steroid and
            thyroid hormones," Bioch. Biophys. Acta 1318(1-2), 173-183, 1997. (Thyroid and progesterone improve
            respiratory efficiency, lowering oxygen consumption which restoring energy production.) R. B. Gibbs, et al.,
            "Effects of estrogen on potassium stimulated acetylcholine release in the hippocampus and overlying cortex
            of adult rats," Brain Res. 749(1), 143-146, 1997. (Increased response.) I. V. Gusakov, et al.,
            "Investigation of the role of free-radical processes in epilepsy and epileptogenesis," Bull. Exp. Biol.
            &amp; Medicine 117(2), 206, 1994.
        </p>
        <p>
            B. K. Shakenova, "A new treatment of epilepsy resistant to traditional antiseizure pharmacotherapy," Bull.
            Exp. Biol. &amp; Medicine 117(2), 227, 1994. (Antihypoxant with antioxidant activity.) R. N. Rzaev and M. N.
            Aliev, "The use of antioxidants in the treatment of tic-accompanied hyperkineses in children," Bull. Exp.
            Biol. &amp; Medicine 117(2), 222, 1994.
        </p>

        <p>
            D. A. Sutkovoi and N. I. Lisyanyi, "Relationship between the kinetics of lipid peroxidation and autoimmune
            reactions after craniocerebral injury," Bull. Exp. Biol. &amp; Medicine 117(2), 2, 1994. Winfried G.
            Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology 30(3/4)
            369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a pituitary site,
            have been determined as concomitants of aging in women." "...aging may impair the negative feedback
            sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of functional
            aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure facilitates the
            loss of hypothalamic neurons...."
        </p>

        <p>
            J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107,
            274-279, 1980. J. Herbert and S. Zuckerman, "Ovarian stimulation from cerebral lesion in ferrets," J.
            Endocrinology 17(4), 433-443, 1958. G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron
            loss: A possible model of hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid
            neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced
            formation of free radicals." "...this beta-endorphin cell loss is followed by a compensatory upregulation of
            mu opioid receptors in the vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results
            "in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic
            effects of estradiol cause a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity."
            Treatment with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian
            cycles" in estrogen-treated rats. G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through
            opioids in postmenopausal women using naloxone," Neuroendocrinology 39, 60-63, 1984.
        </p>
        <p>
            H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative
            stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a
            sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical
            abstracts hydrogen from...NADH to generate the NAD radical." "...the futile metabolism of micromolar
            quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing
            cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence." S. Santagati, et
            al., "Estrogen receptor is expressed in different types of glial cells in culture," J. Neurochem. 63(6),
            2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..." D. X. Liu and L.
            P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo," Free Radical Biol.
            Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic acid
            metabolites...may form a feedback loop in which generation of one type leads to formation of the other."
            "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...." J. Owens and
            P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2 alpha," Brain
            Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its metabolites may bias
            neurons towards excitation." [Estrogen appears to support this excitatory system at every level, while
            prostaglandin F2 alpha alters steroid balance, by suppressing progesterone synthesis.] J. G. Liehr, et al.,
            "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the
            mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995. "... elicits biological
            activities distinct from estradiol, most notably an oxidant stress response induced by free radicals
            generated by metabolic redox cycling reactions."
        </p>
        <p>
            J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8,
            415-423, 1990. P. Aschheim, "Resultats fournis par la greffe heterochrone des ovaires dan l'etude de la
            regulation hypothalamo-hypophyso-ovarienne de la ratte senile," Gerontologia 10, 65-75, 1964/65. "Our last
            experiment, grafting ovaries...into senile rats which had been castrated (ovariectomized) when young, and
            its result, the appearance of estrous cycles, seems explicable by this hypothesis. Everything happens as if
            the long absence of ovarian hormones... had kept the cells of the hypothalamus in the state of youth. It's
            as if the messages of the circulating steroids fatigued the hypothalamic memory." "What are the factors that
            cause this diminution of the hypothalamic sensitivity...? Kennedy incriminates a decrease in the cellular
            metabolism in general...."
        </p>
        <p>
            P. Ascheim, "Aging in the hypothalamic-hypophyseal-ovarian axis in the rat," pp. 376-418 in: A. V. Everitt
            and J. A. Burgess, editors, Hypothalamus, Pituitary and Aging, C. C. Thomas, Springfield, 1976. C. A. Frye
            and J. D. Sturgis, "Neurosteroids affect spatial reference, working, and long-term memory of female rats,"
            Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer to acquire a spatial task during
            behavioral estrus.] (CA Frye, boston univ., dept biol, behavioral neurosci lab, boston 02215)
            "Estrus-associated decrements in a water maze task are limited to acquisition," Physiol. Behav. 57(1), 5-14,
            1995.
        </p>
        <p>
            C. A. Kristensen, et al., "Effect of estrogen withdrawal on energy-rich phosphates and prediction of
            estrogen-dependence monitored by in vivo 31P magnetic resonance spectoscopy of four human breast cancer
            xenografts," Cancer Research 55(8), 1664-1669, 1995. This is a very important confirmation of the idea that
            estrogen, by blocking energy, constrains cell function.
        </p>
        <p>
            A. J. Roberts and L. D. Keith, "Corticosteroids enhance convulsion susceptibility via central
            mineralocorticoid receptors," Psychoneuroendocrinology 20(8), 891-902, 1995. ("...increase corticosterone
            levels are associated with increased severity of ethanol, pentobarbitol, and diazepam withdrawal. Further
            work with chemical convulsants suggests that mineralocorticoid receptors mediate excitatory effects of
            corticosteroids on convulsion susceptibility. The circadian rhythm in convulsion susceptibility varies with
            the circadian rhythm of plasma corticosterone levels and MR binding." "...MR are substantially bound at rest
            and maximally occupied during the circadian peak in corticosteroid levels and during stressor exposure,
            these receptors are implicated in the maintenance of and in changes in the arousal state of animals.") L.
            Murri, et al., "Neuroendocrine evaluation in catamenial epilepsy," Funct. Neurol. 1(4) 399-403, 1986. "Our
            data showed a reduction of luteal phase progesterone secretion; an imbalanced secretion of ovarian steroids
            plays a role in the catamenial exacerbation of epilepsy." S. Bag, et al., "Pregnancy and epilepsy," J.
            Neurol. 236(5), 311-313, 1989.
        </p>
        <p>
            "Patients with increased seizure frequency had significantly higher oestrogen levels, lower level of
            progesterone...." "...abortions and status epilepticus had high serum oestrogen levels." M. I. Balabolkin,
            et al., "The role of the female sex hormones in the pathogenesis of catamenial epileptic seizures," Ter.
            Arkh. 66(4), 68-71, 1994. "...a tendency to deficient luteal phase and relative hyperestrogenemia in all the
            cycle phases." C. A. Guerreiro, "Ovulatory period and epileptic crisis," Arq. Neuropsiquiatr. 49(2),
            198-203, 1991. "We think the estrogen peak is probably the main cause of the increased frequency of
            epileptic seizures during the ovulatory period."
        </p>

        <p>
            U. Bonuccelli, et al., "Unbalanced progesterone and estradiol secretion in catamenial epilepsy," Epilepsy
            Res. 3(2), 100-106, 1989. (Luteal secretion ratio, progesterone to estrogen, was significantly reduced in
            patients versus controls.)
        </p>
        <p>
            T. Backstrom, "Epilepsy in women," Experientia 32(2), 248-249, 1976. "...a significant positive correlation
            between estrogen/progesterone ratio and scores of fits."
        </p>
        <p>
            A. G. Herzog, "Hormonal changes in epilepsy," Epilepsia 36(4), 323-326, 1995. A. G. Herzog, "Progesterone
            therapy in women with partial and secondary generalized seizures," Neurology 45(9), 1660-1662, 1995. A. G.
            Herzog, "Reproductive endocrine considerations and hormonal therapy for women with epilepsy," Epilepsia
            32(Suppl.6), S27-33, 1991. "Seizure frequency varies with the serum estradiol to progesterone ratio." "...
            propensity for onset at menarch and exacerbation of seizures during the months or years leading up to
            menopause..." polycystic ovarian syndrome and hypogonadotropic hypogonadism are significantly
            overrepresented among women with epilepsy.
        </p>
        <p>
            R.H. Mattson and J. A. Cramer, "Epilepsy, sex hormones, and antiepileptic drugs," Epilepsia 26(Suppl. 1),
            S40-51, 1985. There were fewer seizures during the luteal phase but they increased when the progesterone
            level declined.
        </p>
        <p>
            J.J. Jacono and J. M. Robertson, "The effects of estrogen, progesterone, and ionized calcium on seizures
            during the menstrual cycle of epileptic women," Epilepsia 28(5), 571-577, 1987. A positive relation of serum
            estrogen and seizures, negative relation between serum ionized calcium and seizures, and negative relation
            between serum estrogen and calcium. F. E. Jensen, et al., "Epileptogenic effect of hypoxia in the immature
            rodent brain," Ann. Neurol. 29(6),629-836, 1991. E. C. Wirrell, et al., "Will a critical level of
            hyperventilation-induced hypocapnia always induce an absence seizure?" Epilepsia 37(5), 459-462, 1996. A.
            Nehlig, et al., "Absence seizures induce a decrease in cerebral blood flow: Human and animal data," J.
            Cereb. Blood Flow Metab. 16(1), 147-155, 1996.
        </p>

        <p>
            Some clinical laboratory findings in epilepsy: Folic acid, serum decrease, R. E. Davis, et al., "Serum
            pyridoxal, folate, and vitamin B12 levels in institutionalized epileptics," Epilepsia 16, 463-8, 1975.
        </p>
        <p>
            Serum GGT, constantly elevated. Ewen and Griffiths, "Gamma-glutamyl transpeptidase: Elevated activities in
            certain neurologic diseases," Am. J. Clin. Pathol. 59, 2-9, 1973.
        </p>
        <p>
            IgA, CSF decreased, F. Mora, et al.
        </p>
        <p>
            Iron-binding capacity, total, serum decrease. F. Mora, et al. Magnesium, serum, decreased; between seizures.
            C S Babel, et al Prealbumin, CSF, increased, the only protein to increase in epileptics. F. Mora, et al.
        </p>
        <p>
            Pyridoxine, serum, sometimes decreased. R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969.
        </p>

        <p>
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