Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolonged alcohol consumption leads to the development of tolerance to and dependence on ethanol, resulting in a decreased response to the sedative/hypnotic effects of ethanol, and by negative symptomatology following abrupt termination of use. One symptom associated with ethanol withdrawal in humans, as well as laboratory animals, is enhanced susceptibility to seizures. This study investigated the effects of the neurosteroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-5 alpha-THP), on alterations in seizure sensitivity associated with ethanol withdrawal. 3 alpha-5 alpha-THP is a potent anxiolytic and anticonvulsant agent that acts via selective interactions with GABAA receptors. Extensive evidence suggests that some aspects of ethanol dependence and withdrawal are mediated by alterations in GABAA receptor function. Withdrawal from chronic ethanol exposure elicited dramatic increases in seizure susceptibility in male and female rats. Administration of 3 alpha-5 alpha-THP just before seizure threshold determinations blocked the increased seizure susceptibility induced by ethanol withdrawal. Ethanol-withdrawn animals were protected by 3 alpha-5 alpha-THP at a dose that had no effect on control animal seizure thresholds. Moreover, male and female rats displayed differential responses to the seizure-threshold lowering effects of ethanol withdrawal, as well as the protection by 3 alpha-5 alpha-THP pretreatment. These findings suggest that there are gender differences associated both with ethanol withdrawal as well as the protection by 3 alpha-5 alpha-THP in ethanol-dependent rats.
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PMID:The neurosteroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one, protects against bicuculline-induced seizures during ethanol withdrawal in rats. 762 68

The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-THP) acts as a potent allosteric modulator and a direct activator of the GABA-chloride channel complex. This neurosteroid has also been found to protect against seizures that arise from blockade of the GABA-chloride channel complex. Because 3 alpha,5 alpha-THP protects against excitotoxin-induced seizure activity and because seizure activity has been found to be associated with aberrant hippocampal nerve cell growth, the rapid effect of the neurosteroid 3 alpha,5 alpha-THP upon nerve cell growth was investigated using videomicroscopy of hippocampal neurons in culture. Within 40 min of exposure 3 alpha,5 alpha-THP induced a significant decrease in the area and length of neurites. A concomitant decrement in the number and length of filopodia decorating neuritic extensions also occurred within the 40 min of 3 alpha,5 alpha-THP exposure. Both rapid and slow retrograde movement of intracellular organelles was observed in 3 alpha,5 alpha-THP-treated neurons. 3 alpha,5 alpha-THP-induced regression of neuritic extensions occurred only in nerve cells that had not yet established contact with other nerve or glial cells in culture. Established structural connections between neurons or glia did not erode during 3 alpha,5 alpha-THP exposure. Neither the inactive stereoisomer 3 beta-hydroxy-5 beta-pregnan-20-one nor progesterone had a significant effect upon any of the morphological parameters assessed. In approximately 25% of the cells in which 3 alpha,5 alpha-THP had induced regression, subsequent exposure to 17 beta-estradiol induced profuse filopodial growth within 60 sec of exposure. In cultures similar in age to those used in the morphological studies, 3 alpha,5 alpha-THP induced a significant increase in 36Cl- uptake within 10 sec. The magnitude of 36Cl- uptake was comparable to that induced by exposure to 100 microM GABA. In older, more mature cultures in which the nerve cells had established structural connections, 3 alpha,5 alpha-THP protected cells from picrotoxin-induced nerve cell death. These results demonstrate that 3 alpha,5 alpha-THP can induce regression of neuronal morphology within a relatively rapid time frame. 3 alpha,5 alpha-THP induction of 36Cl- uptake within 10 sec suggests that activation of neurosteroid-regulated chloride channels is an initial step in the biochemical mechanism underlying the retraction induced by this progesterone metabolite steroid. In select instances, 17 beta-estradiol induced an extremely rapid reversal of the filopodial regression produced by 3 alpha,5 alpha-THP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one induces cytoarchitectural regression in cultured fetal hippocampal neurons. 791 Feb 1

Some anticonvulsant drugs may suppress seizures by enhancing activity of GABAergic systems. Progesterone (P)'s anti-convulsant and neuroprotective effects may be due to the steroid's actions on GABAA-benzodiazepine receptor complexes (GBRs) rather than intracellular progestin receptors (PRs), as many P metabolites have a greater effect in vitro on benzodiazepine binding and Cl-flux than P, but poor affinity for PRs. If P's actions are due to metabolism to a progestin more potent at GBRs, then systemic administration of one of those P metabolites should also prevent CNS damage. To test this hypothesis male rats were implanted with a bipolar electrode, aimed above the perforant pathway. Experimental animals received the 5 alpha-reduced P metabolite most effective at GBRs, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) 2.5 mg/kg s.c., 3 h prior to perforant pathway stimulation, while control animals received sesame oil vehicle. The duration of chewing and drooling and the incidence of wet dog shakes, partial and full seizures were reduced during perforant pathway stimulation in animals pre-treated with 3 alpha,5 alpha-THP compared to vehicle. Two weeks later, animals pre-treated with 3 alpha,5 alpha-THP had shorter latencies and distances to find a hidden platform in a Morris Water maze task. 3 alpha,5 alpha-THP pre-treatment also reduced damage to CA1 and CA3 layers of the hippocampus and preserved the number of neurons in the hilar region. These data indicate that the neurosteroid metabolite of P, 3 alpha,5 alpha-THP, can have anticonvulsant and may have neuroprotective effects in an animal model of epilepsy. Further, these data suggest that the mechanism of P's protective and anticonvulsant effects may be via GBRs rather than PRs.
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PMID:The neurosteroid 3 alpha, 5 apha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy. 857 58

The anxiolytic and anticonvulsant effects of benzodiazepines, barbiturates, ethanol and neuroactive steroids are mediated by selective interactions with gamma-aminobutyric acidA (GABA(A)) receptors. Chronic ethanol exposure decreases the sensitivity of GABA(A) receptors to benzodiazepines, barbiturates and ethanol. Ethanol withdrawing rats are cross-tolerant to the anticonvulsant effects of benzodiazepines as shown by a 16% decrease in the anticonvulsant efficacy of diazepam compared to controls. In contrast, ethanol withdrawing rats are sensitized to the anticonvulsant effects of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP), exhibiting a 46% increase in the anticonvulsant effect against bicuculline-induced seizures compared to control rats. This effect may involve a change in the sensitivity of GABA(A) receptors to 3 alpha,5 alpha-THP because potentiation of GABA(A) receptor mediated chloride uptake into cerebral cortical synaptoneurosomes is enhanced by 3 alpha,5 alpha-THP up to 50% in ethanol withdrawing rats compared to controls. 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC) potentiation of GABA(A) receptor-mediated chloride uptake is also enhanced during ethanol withdrawal. Moreover, the plasma levels of 3 alpha,5 alpha-THP and progesterone did not differ in ethanol withdrawing rats compared to controls. These alterations in neurosteroid sensitivity were also accompanied by selective alterations in cortical GABA(A) receptor subunit mRNA levels. Levels for the alpha 1 and alpha 4 subunit showed only slight alteration during withdrawal whereas we had previously observed a significant decrease in alpha 1 and a significant increase in alpha 4 mRNA levels in ethanol dependent (not withdrawing) animals. beta 2, beta and gamma 1 mRNA levels significantly increased during ethanol withdrawal. Taken together, these results suggest that ethanol withdrawal produces alterations in GABA(A) receptors that sensitize rats to the pharmacological effects of neuroactive steroids. Because ethanol-dependent or withdrawing rats are tolerant to the intoxicating, anxiolytic and anticonvulsant effects of ethanol and cross-tolerant to many effects of benzodiazepines and barbiturates, sensitization to the effects of neuroactive steroids could have significant therapeutic potential.
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PMID:Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. 876 98

Recent work found that lower endogenous levels of the gamma-aminobutyric acid-agonist, neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) may be correlated with increased ethanol withdrawal severity in the selectively bred Withdrawal Seizure-Prone and -Resistant mice. The present studies were conducted to determine whether decreased sensitivity to 3alpha,5alpha-THP was correlated with ethanol withdrawal hyperexcitability in another genetic mouse model, namely the C57BL/6 (B6) and DBA/2 (D2) inbred strains. These strains also differ in ethanol withdrawal severity (D2 >> B6). B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-10 mg/kg i.p.) 15 min before the timed tail vein infusion of pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anticonvulsant effect of 3alpha,5alpha-THP. Subsequent studies measured sensitivity to several of the pharmacological effects of 3alpha,5alpha-THP. B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-32 mg/kg) before testing for locomotor activation (total number of entries) and anxiolysis (percent open arm entries) on the elevated plus maze, muscle relaxation (impairment of forelimb grip strength), ataxia (impairment of Rotarod performance) and seizure susceptibility to pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anxiolytic, locomotor stimulant and anticonvulsant effects of 3alpha,5alpha-THP. In contrast, D2 mice were more sensitive than B6 mice to 3alpha,5alpha-THP-induced muscle relaxation and ataxia. Plasma 3alpha,5alpha-THP levels did not differ in the B6 and D2 mice injected with this steroid, suggesting that the strain differences were not pharmacokinetic. Collectively, the results in selectively bred Withdrawal Seizure-Prone and -Resistant mice and B6 and D2 inbred strains suggest that genetic differences in neuroactive steroid sensitivity and biosynthesis may contribute to ethanol withdrawal severity.
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PMID:Genetic differences in behavioral sensitivity to a neuroactive steroid. 902 96

The hormone progesterone is readily converted to 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) in the brains of males and females. In the brain, 3alpha,5alpha-THP acts like a sedative, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (gamma-aminobutyric acid), the brain's major inhibitory neurotransmitter. Symptoms of premenstrual syndrome (PMS), such as anxiety and seizure susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3alpha,5alpha-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines and ethanol can also produce PMS-like withdrawal symptoms. Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription. Specifically, this effect was due to reduced levels of 3alpha,5alpha-THP which enhance transcription of the gene encoding the alpha4 subunit of the GABA(A) receptor. We also find that increased susceptibility to seizure after progesferone withdrawal is due to a sixfold decrease in the decay time for GABA currents and consequent decreased inhibitory function. Blockade of the alpha4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABA(A) receptor subunits as a result of progesterone withdrawal.
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PMID:GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. 979 Jan 85

The purpose of the present study was to examine seizure activity during reduced 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) production. Ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes above the perforant pathway; silastic implants filled with estradiol-17-benzoate (EB) and progesterone were inserted subcutaneously to mimic diestrus. Estrus was then induced in half of these animals by injection of EB (30 microg) and progesterone (2.5 mg), 48 and 4 h, respectively, prior to perforant pathway stimulation. Half of the estrous and diestrous rats also received a 5alpha-reductase inhibitor, finasteride (50 mg/kg), 6 h prior to perforant pathway stimulation. The estrous condition was associated with reduced number and duration of partial seizures, improved performance on a Morris water maze recovery of function test, reduced neuronal loss in the hilar region of the hippocampus, and elevated central and plasma 3alpha,5alpha-THP, compared to estrus+finasteride, diestrus+vehicle and diestrus+finasteride conditions, which did not differ from each another. These data suggest antiseizure effects of estrus may be caused, in part, by the action of 3alpha,5alpha-THP and that the precipitous decline in 3alpha,5alpha-THP may restore seizure threshold to control levels.
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PMID:Finasteride blocks the reduction in ictal activity produced by exogenous estrous cyclicity. 963 Mar 99

Ethanol dependence, arising from chronic ethanol exposure, is associated with neuroadaptations of GABAA receptors, evidenced by alterations in various behaviors, receptor responsiveness and subunit gene expression. The present studies explored the effects of ethanol dependence in female rats for comparison with previous studies in our laboratory using male rats. We found that ethanol dependence resulted in differential effects on GABAA receptor gene expression in female rat cerebral cortex compared to ethanol dependent male rats. Notably, chronic ethanol consumption did not change GABAA receptor alpha 1 subunit peptide levels in ethanol dependent female rat cortex, in contrast to previously observed decreases in alpha 1 subunit expression in ethanol dependent male rat cortex. The effects of ethanol dependence on additional GABAA receptor subunit peptide levels (alpha 4, beta 2/3 and gamma 2) were similar, but not identical, between female and male rat cortex. When directly compared within the experiment, male and female rats had similar baseline bicuculline seizure thresholds and displayed a similar increase in seizure susceptibility during ethanol withdrawal. Ethanol withdrawn female rats were cross tolerant to the anticonvulsant effects of diazepam, similar to the findings in ethanol withdrawn male rats. Ethanol withdrawn female rats showed a dose-dependent enhancement of the anticonvulsant effect of the neuroactive steroid, THDOC (3 alpha,21-dihydroxy-5 alpha-pregnan-20-one) compared to control animals. This finding is similar to previous observations of increased sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-THP (3 alpha-hydroxy-5 alpha-pregnan-20-one) in ethanol withdrawn male and female rats. In addition, low dose administration of THDOC elevated seizure thresholds in ethanol withdrawn female but not male rats, suggesting that ethanol withdrawn female rats were more responsive to the anticonvulsant effects of this neurosteroid than were ethanol withdrawn male rats. These findings show that gender impacts on adaptations in GABAA receptors elicited by ethanol dependence. However, the physiological outcomes of the differential alterations are not clear. Taken together, these studies suggest that additional mechanisms, beyond effects on GABAA receptor gene expression are involved in the mediation of ethanol dependence and withdrawal.
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PMID:Influence of gender on chronic ethanol-induced alterations in GABAA receptors in rats. 968 72

Pro-convulsant withdrawal properties have been reported for a variety of GABA-modulatory drugs, such as the benzodiazepines (BDZs, [S.E. File, The history of BDZ dependence: a review of animal studies, Neurosci. Biobehav. Rev. 14 (1990) 135-146; P.R. Finley, P. E. Nolan, Precipitation of BDZ withdrawal following sudden discontinuation of midazolam, DICP 23 (1989) 151-152]), barbiturates and ethanol [N. Kokka, D.E. Sapp, U. Witte, R.W. Olsen, Sex differences in sensitivity to pentylenetetrazol but not in GABAA receptor binding, Pharm. Biochem. Behav. 43 (1992) 441-447]. In this report, we test the hypothesis that pro-convulsant effects are produced by withdrawal from the GABA-modulatory neurosteroid 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) after sustained exposure to elevated circulating levels of its parent compound progesterone (P). Seizure activity was precipitated by picrotoxin or with the BDZ inverse agonist n-methyl-beta-carboline-3-carboxamide (beta-CC), and a seizure rating determined 24 h after abrupt discontinuation of P following a multiple withdrawal/chronic administration paradigm. In some cases, a pseudopregnant rat model was employed to produce increased ovarian production of P prior to withdrawal (ovariectomy). Rats undergoing P withdrawal exhibited greater seizure-like activity than vehicle-treated controls, and received seizure scores in the same range as rats undergoing BDZ withdrawal. Administration of a 5alpha-reductase blocker, MK-906, along with P, prevented this pro-convulsant effect of P withdrawal, suggesting that the GABA-modulatory 3alpha,5alpha-THP is the active compound responsible for this withdrawal effect. Combined administration of P and diazepam produced synergistic effects upon withdrawal and produced a seizure score higher than observed after withdrawal from either agent alone. These results suggest that P exhibits withdrawal properties via the neuroactive steroid 3alpha, 5alpha-THP, that include exacerbation of seizure activity. These results may have clinical relevance, as increased incidence and severity of seizures has been reported in susceptible women during times of declining circulating levels of P across the menstrual cycle [T. Backstrom, B. Zetterlund, S. Blom, M. Romano, Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy, Acta Neurol. Scand. 69 (1984) 240-248; A.G. Herzog, Progesterone therapy in women with complex partial and secondary generalized seizures, Neurology 45 (1995) 1660-1662].
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PMID:Progesterone withdrawal I: pro-convulsant effects. 975 4

Previous results from this lab have demonstrated that the GABA-modulatory steroid 3alpha-OH-5alpha-pregnan-20-one (3alpha, 5alpha-THP) exhibits withdrawal properties, increasing anxiety [M.A. Gallo, S.S. Smith, Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: a possible rat model of PMS anxiety, Pharmacol. Biochem. 46 (1993) 897-904.] and seizure susceptibility [S.S. Smith, Q.H. Gong, F.-C. Hsu, R.S. Markowitz, J. M.H. ffrench-Mullen, X. Li, GABAA receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid, Nature 392 (1998) 926-930.] upon abrupt discontinuation after chronic administration of its parent compound, progesterone (P), in a manner similar to other GABA-modulatory drugs. Further, we have demonstrated that withdrawal from P produces insensitivity to the potentiating effects of the benzodiazepine (BDZ) lorazepam (LZM) on GABA-gated Cl- current [A.-M.N. Costa, K.T. Spence, S.S. Smith, J.M. H. ffrench-Mullen, Withdrawal from the endogenous steroid progesterone results in GABAA currents insensitive to BDZ modulation in rats CA1 hippocampus, J. Neurophysiology 74 (1995) 464-469; S.S. Smith, Q.H. Gong, F.-C. Hsu, R.S. Markowitz, J.M.H. ffrench-Mullen, X. Li, GABAA receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid, Nature 392 (1998) 926-930.], assessed using whole cell patch clamp procedures on pyramidal neurons acutely dissociated from CA1 hippocampus. The purpose of the present study was to examine the withdrawal effects of P on the sedative potency of LZM, tested behaviorally as the ability to maintain position on a variable speed treadmill following LZM administration (0.75 mg/kg). Both continuous (continuous release P capsule, single withdrawal) as well as discontinuous (multiple P injection, multiple withdrawal) paradigms were tested. Longer continuous release paradigms were more effective in abolishing the sedative effects of LZM, without producing a change in baseline response. The LZM insensitivity observed following the multiple withdrawal paradigm was prevented by prior intraventricular administration of antisense oligonucleotide against the alpha4 subunit of the GABAA receptor. These results support the hypothesis that withdrawal from P decreases the behavioral response to LZM as a direct result of increases in the alpha4 subunit of the GABAA receptor. Withdrawal from P occurs endogenously during pre-menstrual and post-partum periods, when decreased response to BDZ has been reported.
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PMID:Progesterone withdrawal. II: insensitivity to the sedative effects of a benzodiazepine. 975 6


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