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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The administration of ethanol on a chronic intermittent regimen (CIE) involving multiple withdrawal episodes is a model for ethanol dependence. After CIE, rats exhibited reduced seizure threshold, increased anxiety, tolerance to GABAergic sedative-hypnotic drugs, and changes in GABA(A) receptor function and subunit composition in hippocampus. Previous studies have shown that acute and chronic ethanol may induce changes in the levels of the neurosteroid 3alpha-hydroxysteroid-5alpha-pregnan-20-one (3alpha, 5alpha-THP) in the brain. Therefore, the current study analyses the correlation between chronic intermittent ethanol effects on the level of 3alpha, 5alpha-THP in hippocampus of CIE rats and the behavioral changes in sensitivity to neurosteroids. After CIE, the levels for 3alpha, 5alpha-THP were significantly reduced in hippocampus of rats. The mRNA levels for the enzymes 5alpha-reductase and 3alpha-HSD in hippocampus were also reduced. In vivo, (in contrast to a tolerance to the hypnotic effect of steroids), CIE rats showed increased sensitivity to the anticonvulsant and to the anxiolytic effect of the steroid alphaxalone. Perhaps, this is a response to lowered levels of endogenous neuroactive steroids. CIE rats also showed impairment of hippocampus-dependent memory function. These results suggest that changes in neurosteroids level and in vivo sensitivity to these compounds are involved in the development of ethanol dependence in the CIE model.
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PMID:Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function. 1497 81

Of the many people that have epilepsy, only about 70% achieve seizure control with traditional pharmacotherapies. Steroids have long been known to influence ictal activity and may have a therapeutic role. This review summarizes recent investigations that have enhanced knowledge of the effects and mechanisms of gonadal, adrenal, and neuroactive steroids on seizure processes. Progesterone, which varies across reproductive cycles, pregnancy, and as a function of aging, has been shown to have anti-seizure effects among women with epilepsy and in animal models of epilepsy. Further, data suggest that progesterone's anti-seizure effects may involve its metabolism to the neuroactive steroid, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP), and its subsequent actions at GABA(A) receptors. Androgens also have anti-seizure effects. Androgens' anti-seizure effects may be mediated, in part, through actions of the testosterone metabolite, and neuroactive steroid, 5 alpha-androstane-3 alpha,17 alpha-diol (3 alpha-diol) at GABA(A) receptors. Stress can alter seizure susceptibility, suggesting a role of adrenal steroids on seizure processes. In animal models of epilepsy, acute or chronic stress can increase ictal activity. Notably, stress and seizures can alter levels of gonadal, adrenal, and neuroactive steroids, which may then influence subsequent seizure activity. Thus, this review summarizes recent progress in the role of gonadal, adrenal, and/or neuroactive steroids in seizure processes which suggest that greater understanding of these steroids' effects and mechanisms may ultimately lead to improved seizure control for people with epilepsy.
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PMID:Gonadal, adrenal, and neuroactive steroids' role in ictal activity. 1505 47

Progestins have neuroprotective effects in several in vitro models of neurodegeneration and in vivo in seizure models. The extent to which progesterone's in vivo protective effects may generalize to models not involving seizure processes and whether progesterone's protective effects are modulated by its metabolites have not been comprehensively investigated. The present experiments investigated the effects of progesterone and its metabolites, dihydryoprogesterone (DHP) and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), to protect the hippocampus from damage induced by adrenalectomy (ADX). In Experiments 1 and 2, progesterone, DHP, or 3alpha,5alpha-THP administration (1 mg/kg sc) to female (Experiment 1) or male (Experiment 2) rats similarly reduced the total number of ADX-induced pyknotic cells in the dentate gyrus compared with vehicle administration. In Experiment 3, blocking progesterone's metabolism to 3alpha,5alpha-THP with coadministration of a 5alpha-reductase inhibitor, finasteride (10 mg/kg sc), in female rats attenuated progesterone's protective effects on cell death in the dentate gyrus. Together, these data suggest that progestins can protect against ADX-induced cell death and that the actions of the progesterone metabolite, 3alpha,5alpha-THP, may underlie these effects.
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PMID:3alpha,5alpha-THP mediates progestins' effects to protect against adrenalectomy-induced cell death in the dentate gyrus of female and male rats. 1525 Dec 59

Progesterone has antiseizure effects, which may be due to the actions of its 5alpha-reduced metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Whether metabolism of progesterone to 3alpha,5alpha-THP in the hippocampus is essential for its antiseizure effects was investigated. In Experiment 1, ovariectomized rats were administered subcutaneous progesterone (500 microg) or vehicle (sesame oil), followed 1 hour later by subcutaneous administration of an inhibitor of the 5alpha-reductase enzyme, finasteride (50 mg/kg), or vehicle (90% sesame oil, 10% ethanol). Administration of progesterone increased the latency to, and decreased the number of, tonic seizures and increased hippocampal 3alpha,5alpha-THP levels, compared with vehicle. Administration of finasteride with progesterone attenuated progesterone's antiseizure effects and decreased levels of 3alpha,5alpha-THP in the hippocampus. Finasteride administration alone did not alter ictal behavior or 3alpha,5alpha-THP levels compared with vehicle. In Experiment 2, ovariectomized rats were administered subcutaneous progesterone (500 microg) or vehicle (sesame oil), followed 1 hour later by bilateral infusions of finasteride (10 microg) or vehicle (beta-cyclodextran) into the hippocampus. Administration of finasteride to the hippocampus of progesterone-primed rats significantly increased ictal activity and decreased hippocampal 3alpha,5alpha-THP levels, compared with progesterone administration alone. These data suggest that formation of 3alpha,5alpha-THP in the hippocampus is important for progesterone's antiseizure effects.
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PMID:Attenuating 5alpha-pregnane-3alpha-ol-20-one formation in the hippocampus of female rats increases pentylenetetrazole-induced seizures. 1571 Feb 96

Ketogenic diet (KD) is used to manage intractable epilepsy; however, the mechanisms underlying its therapeutic effects are not known. Steroid hormones, such as progesterone and testosterone, are derived from cholesterol, and are readily 5alpha-reduced to dihydroprogesterone and dihydrotestosterone, which are subsequently converted to 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) and 3alpha-androstanediol, neuroactive steroids that can influence seizures. The present study examined the effects of the KD on circulating concentrations of these neuroactive steroids, and their precursors, in intact female rats. Thirty-six, 22-day-old female Sprague-Dawley rats (weaned at 21 days) were fasted for 8 hours prior to placement on one of three dietary regimens for 6 weeks: ad libitum chow, calorie-restricted chow, or KD. After 6 weeks of the diet, when six rats in each dietary condition were in diestrus and six were in behavioral estrus, all rats were administered pentylenetetrazole (PTZ, 70 mg/kg, i.p.). The latency and incidence of seizures were recorded by an observer who was uninformed of the estrous cycle and dietary treatment conditions of the rats. Immediately after each test, trunk blood was obtained for later measurement of pregnane (progesterone, dihydroprogesterone, 3alpha,5alpha-THP) and androstane (testosterone, dihydrotestosterone, 3alpha-androstanediol) neuroactive steroid concentrations in plasma by radioimmunoassay. KD tended to lengthen the latency to, and significantly reduced the number of, PTZ-induced barrel roll seizures. KD also significantly reduced plasma levels of the pregnane (dihydroprogesterone, 3alpha,5alpha-THP) and androstane (dihydrotestosterone, 3alpha-androstanediol) 5alpha-reduced metabolites. These data suggest that levels of pregnane and androstane neuroactive steroids, or their precursors, may underlie some of the antiseizure effects of KD.
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PMID:Ketogenic diet decreases circulating concentrations of neuroactive steroids of female rats. 1605 40

Neurosteroids, such as the progesterone metabolite 3alpha-OH-5alpha[beta]-pregnan-20-one (THP or [allo]pregnanolone), function as potent positive modulators of the GABA(A) receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sustained levels of inhibition. A number of laboratories have demonstrated that both chronic administration of THP as well as its withdrawal transiently increase expression of the alpha4 subunit of the GABAR in several areas of the central nervous system (CNS) as well as in in vitro neuronal systems. Receptors containing this subunit are insensitive to benzodiazepine (BDZ) modulation and display faster deactivation kinetics, which studies suggest underlie hyperexcitability states. Similar increases in alpha4 expression are triggered by withdrawal from other GABA-modulatory compounds, such as ethanol and BDZ, suggesting a common mechanism. Other studies have reported puberty or estrous cycle-associated increases in delta-GABAR, the most sensitive target of these steroids which underlies a tonic inhibitory current. In the studies reported here, the effect of steroids on inhibition, which influence anxiety state and seizure susceptibility, depend not only on the subunit composition of the receptor but also on the direction of Cl(-) current generated by these target receptors. The effect of neurosteroids on GABAR function thus results in behavioral outcomes relevant for pubertal mood swings, premenstrual dysphoric disorder and catamenial epilepsy, which are due to fluctuations in endogenous steroids.
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PMID:Neurosteroid regulation of GABA(A) receptors: Focus on the alpha4 and delta subunits. 1751 83

In this study, delta(13)C(V- PDB) and delta(15)N(AIR) values of 132 cocaine samples from a big seizure in Germany in 2002 were determined using elemental analyser isotope ratio mass spectrometry. The 1.2 tons of cocaine were packed in 1 kg packages and the cocaine bricks inside these packages showed certain logos. Twenty different logos could be identified. Results show a large variability among some samples, for delta(15)N(AIR) values ranging from-17 to -2 per thousand. Furthermore, the possibility of linking samples with the same logo was checked. The results show that, in general, there is no relationship between the determined isotope ratio and a certain logo.
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PMID:Determination of delta13 CV-PDB and delta15NAIR values of cocaine from a big seizure in Germany by stable isotope ratio mass spectrometry. 1804 18

Sex steroids can influence seizures. Estrogen (E(2)), progesterone (P(4)), and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), in particular, have received much attention for exerting these effects. Typically, it is thought that E(2) precipitates seizures, and progestogens, such as P(4) and 3alpha,5alpha-THP, attenuate seizures. However, E(2) may also have antiseizure effects, perhaps in part through its enhancement of the formation of 3alpha,5alpha-THP, which has GABA(A)/benzodiazepine receptor agonist-like actions. To test this hypothesis, male and female, castrated or ovariectomized, wild-type and 5alpha-reductase knockout mice were implanted with Silastic capsules of E(2) or vehicle and then administered pentylenetetrazol (85 mg/kg, ip). Wild-type, but not 5alpha-reductase knockout, mice administered E(2) had significantly longer latencies to myoclonus and increased levels of 3alpha,5alpha-THP in the hippocampus. Thus, some of the anticonvulsive effects of E(2) may involve formation of 3alpha,5alpha-THP in the hippocampus.
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PMID:Estrogen increases latencies to seizures and levels of 5alpha-pregnan-3alpha-ol-20-one in hippocampus of wild-type, but not 5alpha-reductase knockout, mice. 1978 46

Neurosteroids such as allopregnanolone (THP) act as positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors and have exerted anticonvulsant properties. However, their role in the regulation of epileptogenesis is unclear. It has been shown that circulating levels of THP fluctuate during development and seizure episodes. Furthermore, both chronic administration of THP and its withdrawal transiently increase expression of the alpha4 subunit of the GABAA receptor in the brain. The steroidogenic enzymes, 5-alpha-reductase (5aR) and 3-alpha-hydroxysteroid dehydrogenase (3aHSD) have been identified as well, indicating that various cell types are involved in the biosynthesis of neuroactive steroids in the brain. The purpose of the present study is to examine how GABAA receptor-modulating neurosteroids contribute to the epileptogenesis by using the epileptic mutant EL mouse. Male EL mice and control animals, DDY mice, were used. EL mice show secondary generalized seizures, which initiate primarily at the parietal cortex and generalize through the hippocampus. In the interictal period during development, changes of THP, 5aR, 3aSDH, and GABAA receptor alpha4, gamma2, and delta subunits were investigated by western blotting in the hippocampus. In EL mice, levels of the neurosteroid THP and the steroidogenic enzymes 5aR and 3aSDH significantly increased at 3 weeks of age, and rapidly decreased thereafter (5-10 weeks). The sharp withdrawal was observed before mice experienced frequent seizures. In contrast, GABAA alpha4, gamma2, and delta expressions were upregulated (3-8 weeks). In the brain of EL mice, positive neurosteroids such as THP were withdrawn before mice experienced repetitive seizures, which may likely be a trigger for ictogenesis and epileptogenesis. Furthermore, reorganization of the GABAA receptor subunits may lead to a hypersensitivity of the receptor to neurosteroids. Therefore, GABAA receptor-regulating neurosteroids may be a promising target for the development of novel antiepileptic agents.
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PMID:New therapeutic approaches for epilepsies, focusing on reorganization of the GABAA receptor subunits by neurosteroids. 2061 18

Steroid hormones, such as progestogens and androgens, influence seizures. Progestogens and androgens exert organizational and/or activational effects that may mitigate vulnerability to, and/or expression of, some seizure disorders. Progestogens, such as progesterone (P(4)) and its 5alpha-reduced metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), which vary across the reproductive cycle and lifespan, may protect against seizures through actions at intracellular progestin receptors (PRs) and membrane receptors, such as gamma-aminobutyric acid (GABA)(A) receptors. Similarly, androgens, such as testosterone (T), which also vary across the reproductive cycle and the lifespan, can have antiseizure effects. Some of these effects of T may be due to aromatization to estrogen and/or 5alpha-reduction to dihydrotestosterone (DHT), and its subsequent conversion through 3alpha-hydroxysteroid dehydrogenase to 5alpha-androstane-3alpha,17alpha-diol (3alpha-diol). Sensitivity to steroids in some individuals may be mitigated by differences in stress, developmental phase, reproductive status, endocrine status, and treatments, such as antiepileptic drugs (AEDs), which alter levels of these ligands and/or function of their target sites. The evidence implicating sex steroids in differences associated with hormonal, reproductive, developmental, stress, seizure type, and/or therapeutics are discussed.
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PMID:Effects and mechanisms of progestogens and androgens in ictal activity. 2061 19


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