Date: Wed, 30 Nov 94 17:50:20 -0500 From: Bob Broedel To: als@huey.met.fsu.edu Subject: ALSD#154 ALS-ON-LINE =============================================================== == == == ----------- ALS Interest Group ----------- == == ALS Digest (#154, 30 November 1994) == == == == ------ Amyotrophic Lateral Sclerosis (ALS) == == ------ Motor Neurone Disease (MND) == == ------ Lou Gehrig's disease == == ------ Charcot's Disease == == == == This e-mail list has been set up to serve the world-wide == == ALS community. That is, ALS patients, ALS researchers, == == ALS support/discussion groups, ALS clinics, etc. Others == == are welcome (and invited) to join. The ALS Digest is == == published (approximately) weekly. Currently there are == == 410+ subscribers. == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == Sorry, but this is *not* a LISTSERV setup. == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. ALS, neurosteroids (1) ===== ALS, neurosteroids ========== Date : 29 Nov 94 00:25:20 EST >From : Wayne Phillips <70303.173@compuserve.com> Subject: ALS, neurosteroids I have been taking progesterone oraly for several months; it has noticably reduced my cramping and eliminated my insomnia. While under my endocrinologist's supervision I took doses of 5 and 10 mg. at bedtime and 20 mg. 3 times daily (60 per day total). (He said 20 to 40 at 3 times daily is typical for treating sleep apnea, so 5 is pretty small.) I noticed no difference between doses initially. On the fourth day after decreasing my dose I would have a couple of days of intense cramping which would then subside. After stopping completely, my cramping and insomnia would return to pre-treatment levels. insomnia pre-treatment: go to bed, lay awake for 1 to 2 hours, sleep lightly 2 hours, lay awake 1 to 4 hours, sleep heavily 2 to 3 hours progesterone: go to bed, usually asleep within 30 minutes, sleep heavily for up to 9 hours, except when waking to turn over; after a couple of months on 5 mg. my insomnia returned slightly, but going to 10 fixed it cramping pre-treatment: tongue, neck during daytime; abdominals, intercostals especially after a sneeze or cough; calves, thighs at night (though less intense than earlier in my illness) progesterone: reduced intensity in tongue, neck; little or no cramping in abdominals, intercostals, calves, thighs I am a 110 lb. male with sporadic, limb onset, early onset (age 29) ALS. I'm just reporting, not recommending treatment (disclaimer!). You need to see your doctor if you want to try it since progesterone requires a prescription (in the U.S.). My illness may have a different cause than yours, so it may effect you differently. It may confuse or halt the menstrual cycles of pre-menopausal women. It's inexpensive and readily available. I've noticed no difference between Provera brand and generic. A month's supply at 5 mg./day costs about $6 U.S. "Why hasn't your doctor (or you) published this?" It's annecdotal (not the result of a controlled study) and cramping and insomnia are difficult, maybe impossible, to quantify. It's hard to tell if it has slowed my illness. It would be interesting to see if it significantly extends the life of the new ALS-like transgenic mice. THE THEORY: While searching Medline for "steroid? and neuron?" I saw some papers on "neurosteroids". Neurosteroids (pregnenalone, progesterone, dehydroepiandrosterone) are created in glial cells in the CNS. They and their metabolites have neuroprotective qualities. This includes protection against glutamate toxicity (3,8,25), which has been implicated in ALS. Progesterone inhibits the stimulatory effects of the neurotransmitter acetylcholine(4), and modulates the responsiveness of GABA receptors (7-9,14,19,20,24-26). Any or all of these may explain the results. Insomnia is common in ALS, but in what I've read it's usually attributed to inactivity. But if neurosteroids play a part in sleep cycles, there may be a connection. Steroids have long been known for their anesthetic effects. Insomnia is a logical, though unproven, result of a CNS bathed in excess excitatory amino acids. Below are related references, some with abstracts, from Medline. Note that none of these addresses the issue of what promotes formation of these hormones in glial cells. They don't include this year's research, which I haven't gone over yet. Giving thanks, Wayne 1. Neurosteroids: a new function in the brain. Baulieu EE Communications Hormonales (U 33) INSERM and Biochimie Hormonale, Faculte de Medecine Paris-Sud, Bicetre, France. Biol Cell 1991, 71 (1-2) p3-10 "Neurosteroids" accumulate in the central nervous system independently of supply by peripheral endocrine glands. Dehydroepiandrosterone (DHA) and pregnenolone (delta 5P) were first found in the rat brain. Then, a steroid biosynthetic pathway was demonstrated in oligodendrocytes, mostly by enzyme immunocytochemistry and biochemical studies in primary cultures of glial cells, where the formation, from appropriate radioactive precursors, of delta 5P, delta 5-pregn-3 beta, 20 alpha-diol (20 alpha-DH delta 5P), progesterone (P), 5 alpha-pregnane-3,20-dione (5 alpha-DHP) and 3 alpha-hydroxy-5 alpha-pregnane-20-one (3 alpha, 5 alpha-THP), as well as estrogen-induced nuclear progesterone receptor (PR) was observed. Several biological effects of neurosteroids have been observed, such as electrical stimulation of neurones, involvement in behaviorial activities, modulation of GABAA-receptor (GABAA-R) function (potentiated by 3 alpha, 5 alpha-THP and its 21-hydroxyderivative, antagonized by delta 5P- and DHA-sulfates) and growth/differentiation of glial cells in vitro. Preliminary findings suggest that the neurosteroid concept applies to all mammalian species, including man. Further investigations should assess the pathophysiological significance of the synthesis of neurosteroids and decipher their mechanisms of action via nuclear and membrane receptors. ( 57 Refs.) 2. Neurosteroids: a new brain function? Baulieu EE; Robel P Communications Hormonales (U33), INSERM, Bicetre, France. J Steroid Biochem Mol Biol Nov 20 1990, 37 (3) p395-403 The biosynthesis of neurosteroids proceeds through cholesterol side- chain cleavage, and gives rise to pregnenolone (P) and dehydroepiandrosterone (D). These steroids accumulate in the rat brain independently of the supply by peripheral endocrine glands. This led to the discovery of a steroid biosynthesis pathway in rat brain oligodendrocytes based on enzyme immunocytochemistry and conversion of radioactive precursors to C-21 steroids. Several biological functions have been proposed for P and D. They may serve as precursors of other steroids (such as progesterone and testosterone and their metabolites). They are implicated in the control of some behavioural activities. They have excitatory effects on neurons, and they modulate the function of GABAA-receptors. These observations may apply to all mammalian species including the human, and the physiological significance of neurosteroid synthesis needs further investigation. The relationship between steroids and cerebral function may be reconsidered in the light of a new fact: the existence of a biosynthetic pathway of these compounds from cholesterol, assured in the brain by the oligodendrocytes, glial cells which synthesize myelin. (32 Refs.) 3. Steroid hormones protect spinal cord neurons from glutamate toxicity. Ogata T; Nakamura Y; Tsuji K; Shibata T; Kataoka K Department of Physiology, Ehime University, School of Medicine, Japan. Neuroscience (ENGLAND) Jul 1993, 55 (2) p445-9 The effects of steroid hormones on glutamate neurotoxicity were examined in cultured spinal cord neurons. The extent of neuronal damage, produced by glutamate exposure for 15 min, was estimated based on the activity of lactate dehydrogenase released from degenerated neurons to the media during 24 h of post-exposure incubation. This damage was dependent on the glutamate concentrations used. The addition of dexamethasone, a synthetic steroid, in post-exposure media remarkably reduced the extent of damage in a dose-dependent manner. The half effective concentration for the steroid was approximately 0.7 microM, which was in the range of pharmacological concentration. Dexamethasone was effective even when it was added 2 h after glutamate exposure. Some endogenous steroid hormones--aldosterone, progesterone and testosterone --also showed similar neuroprotective effects. However, cholesterol, a precursor of these steroid hormones, had no effect on glutamate neurotoxicity. This direct protective effect on neurons against glutamate neurotoxicity may explain, at least partly, the mechanisms of beneficial effects of steroid hormones on in vivo spinal cord injury. 4. Progesterone modulates a neuronal nicotinic acetylcholine receptor. Valera S; Ballivet M; Bertrand D Department of Biochemistry, Sciences II, Centre Medical Universitaire, Geneva, Switzerland. Proc Natl Acad Sci U S A Oct 15 1992, 89 (20) p9949-53, The major brain nicotinic acetylcholine receptor is assembled from two subunits termed alpha 4 and n alpha 1. When expressed in Xenopus oocytes, these subunits reconstitute a functional acetylcholine receptor that is inhibited by progesterone levels similar to those found in serum. In this report, we show that the steroid interacts with a site located on the extracellular part of the protein, thus confirming that inhibition by progesterone is not due to a nonspecific perturbation of the membrane bilayer or to the activation of second messengers. Because inhibition by progesterone does not require the presence of agonist, is voltage-independent, and does not alter receptor desensitization, we conclude that the steroid is not an open channel blocker. In addition, we show that progesterone is not a competitive inhibitor but may interact with the acetylcholine binding site and that its effect is independent of the ionic permeability of the receptor. 5. Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons. Bowlby MR Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115. Mol Pharmacol (UNITED STATES) May 1993, 43 (5) p813-9 6. The 5 alpha-reductase in the brain: molecular aspects and relation to brain function. Celotti F; Melcangi RC; Martini L Department of Endocrinology, University of Milan, Italy. Front Neuroendocrinol (UNITED STATES) Apr 1992, 13 (2) p163-215 7. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Majewska MD Laboratoryof Neuropharmacology, NIDA, Baltimore, MD. Prog Neurobiol 1992, 38 (4) p379-95 The abundant CNS cholesterol and its sulfate derivative serve as precursors of different neurosteroids, which bidirectionally modulate neuronal excitability, by potentiating or inhibiting function of the GABAA receptors. The regulation of GABAA receptors in the CNS by the steroids of central or peripheral origin may constitute a vital means of brain-body communication, essential for integrated whole organism responses to external stimuli or internal signals. Modulation of the brain GABA receptors by neurosteroids may form the basis of a myriad of psychophysiological phenomena, such as memory, stress, anxiety, sleep, depression, seizures and others. Therefore, the aberrant synthesis of centrally-active steroids may contribute to defects in neurotransmission, resulting in a variety of neural and affective disorders. The biosynthesis of neurosteroids may also be altered by diet and certain psychotropic drugs, thereby affecting excitation of neurons. Hereditary differences in the level of synthesis and catabolism of different neurosteroids may underlie individual variations in CNS excitability, contributing to differences in personality traits, including the inherited susceptibility to drug addition. (127 Refs.) 8. Progesterone administration attenuates excitatory amino acid responses of cerebellar Purkinje cells. Smith SS Department of Anatomy, Hahnemann University, Philadelphia, PA 19102. Neuroscience 1991, 42 (2) p309-20 We have previously shown that the sex steroid progesterone plays a modulatory role in amino acid physiology by suppressing excitatory responses of cerebellar Purkinje cells to glutamate and augmenting inhibitory responses of these neurons to GABA. In the present study using the rat, progesterone effects on neuronal responses to the specific excitatory amino acid agonists quisqualate, kainate and N-methyl-D- aspartate were tested using iontophoretic, extracellular single unit recording techniques. In addition, the effect of systemic administration of progesterone on quisqualate-evoked excitation was evaluated in the presence of the GABAA blocker bicuculline. Progesterone consistently attenuated excitatory neuronal responses to local application of all three excitatory amino acids by 40-51%, but exerted variable effects on combined administration of quisqualate and N-methyl-D-aspartate which were dependent on temporal and dose-related factors. Progesterone- induced attenuation of the quisqualate response was found to be mediated primarily by a non-N-methyl-D-aspartate receptor. In addition, bicuculline application did not block progesterone effects on quisqualate excitation, suggesting that the observed steroidal modulation of excitatory amino acid function is not secondary to progesterone-induced potentiation of GABA inhibition. 9. Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor. Demirgoren S; Majewska MD; Spivak CE; London ED Neuropharmacology Laboratory, National Institute on Drug Abuse, Baltimore, MD 21224. Neuroscience 1991, 45 (1) p127-35 10. Diazepam binding inhibitor (DBI): a peptide with multiple biological actions. Costa E; Guidotti A Fidia-Georgetown Institute for the Neurosciences, Georgetown University School of Medicine, Washington, D.C. 20007. Life Sci 1991, 49 (5) p325-44 (notes similarities among glial and other steroid producing cells) 11. Non-genomic and genomic effects of steroids on neural activity. McEwen BS Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021. Trends Pharmacol Sci Apr 1991, 12 (4) p141-7 Steroid hormones are recognized as producing their major long-term effects on cell structure and function via intracellular receptors acting on the expression of genes. There is now increasing evidence that steroids also affect the surface of cells and alter ion permeability, as well as release of neurohormones and neurotransmitters. Progesterone appears to be one of the most active of the steroids, and its naturally produced metabolites and some synthetic analogs show activities that are different from the parent steroid. Other steroids, such as estrogens and adrenal steroids and their naturally produced and synthetic analogs, also show membrane effects. Bruce McEwen reviews evidence that synergistic interactions occur between non-genomic and genomic actions of steroids. (37 Refs.) 12. Differential localization of the 5 alpha-reductase and the 3 alpha-hydroxysteroid dehydrogenase in neuronal and glial cultures. Melcangi RC; Celotti F; Castano P; Martini L Department of Endocrinology, University of Milan, Italy. Endocrinology (UNITED STATES) Mar 1993, 132 (3) p1252-9 13. Aromatase activity in cultured brain cells: difference between neurons and glia. Negri Cesi P; Melcangi RC; Celotti F; Martini L Department of Endocrinology, University of Milan, Italy. Brain Res Sep 4 1992, 589 (2) p327-32 14. The actions of endogenous and synthetic pregnane steroids on GABAA receptors. Hill-Venning C; Lambert JJ; Peters JA; Hales TG; Gill C; Callachan H; Sturgess NC Department of Pharmacology and Clinical Pharmacology, University of Dundee, Ninewells Hospital and Medical School, Scotland, U.K. Adv Biochem Psychopharmacol 1992, 47 p93-102 15. Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons. Irwin RP; Maragakis NJ; Rogawski MA; Purdy RH; Farb DH; Paul SM Section on Molecular Pharmacology, NIMH, NINDS, Bethesda, MD 20892. Neurosci Lett Jul 6 1992, 141 (1) p30-4 16. The interaction of steroids with inhibitory and excitatory amino acid receptors. Hill-Venning C; Peters JA; Lambert JJ Department of Pharmacology and Clinical Pharmacology, University of Dundee, Scotland. Clin Neuropharmacol 1992, 15 Suppl 1 Pt A p683A-684A 17. Neurosteroids: biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain. Akwa Y; Young J; Kabbadj K; Sancho MJ; Zucman D; Vourc'h C; Jung-Testas I; Hu ZY; Le Goascogne C; Jo DH; et al INSERM U33, Laboratoire des Hormones, Bicetre, France. J Steroid Biochem Mol Biol 1991, 40 (1-3) p71-81 18. The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor. Majewska MD; Demirgoren S; Spivak CE; London ED Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224. Brain Res Aug 27 1990, 526 (1) p143-6 19. Steroid regulation of the GABAA receptor: ligand binding, chloride transport and behaviour. Majewska MD Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224. Ciba Found Symp 1990, 153 p83-97; discussion 97-106 20. Steroid modulation of the GABAA receptor complex: electrophysiological studies. Lambert JJ; Peters JA; Sturgess NC; Hales TG Department of Pharmacology & Clinical Pharmacology, Ninewells Hospital & Medical School, Dundee University, UK. Ciba Found Symp 1990, 153 p56-71; discussion 71-82 21. Effects of progesterone and its metabolites on neuronal membranes. Ramirez VD; Dluzen DE; Ke FC Department of Physiology and Biophysics, University of Illinois, Urbana 61801. Ciba Found Symp 1990, 153 p125-41; discussion 141-4 22. Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters. Smith SS; Waterhouse BD; Woodward DJ Department of Physiology and Biophysics, Hahnemann University, Philadelphia, PA 19102-1192. Brain Res Sep 29 1987, 422 (1) p52-62 23. Locally applied progesterone metabolites alter neuronal responsiveness in the cerebellum. Smith SS; Waterhouse BD; Woodward DJ Brain Res Bull Jun 1987, 18 (6) p739-47 24. Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. Harrison NL; Majewska MD; Harrington JW; Barker JL J Pharmacol Exp Ther Apr 1987, 241 (1) p346-53 25. Progesterone alters GABA and glutamate responsiveness: a possible mechanism for its anxiolytic action. Smith SS; Waterhouse BD; Chapin JK; Woodward DJ Brain Res Jan 6 1987, 400 (2) p353-9 26. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Majewska MD; Harrison NL; Schwartz RD; Barker JL; Paul SM Science May 23 1986, 232 (4753) p1004-7 27. Steroids in relation to epilepsy and anesthesia. Backstrom T; Gee KW; Lan N; Sorenson M; Whalstrom G Ciba Found Symp 1990, 153 p225-230; discussion 230-9 === end of als 154 ===