UMLS:C0036572 - FACTA Search

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

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

It has been found that the latency of epileptic seizures caused by glutamate decarboxylase (GAD) inhibitor 3-mercaptopropionate (3-MPA) is markedly longer in immature rats than in the adults. Time course of rat brain GAD inhibition was studied in 12-day-old and adult (90-day-old) animals following 3-MPA (70 mg/kg i.p.). GAD activity was determined by quantification of 14CO2 liberated from [1-(14)C]glutamate by supernatant 20,000 x g of brain homogenate prepared from rats killed at different intervals after 3-MPA administration. In adult rats, the enzyme activity decreased significantly by 14.1% even 1 min after 3-MPA administration and was decreasing gradually till the onset of seizures. In immature rats, GAD activity decrease after 1 min was by 41.4% and further decrease was smaller. Comparison of the time profiles of GAD changes in both groups confirmed our findings that in spite of delayed seizure onset, GAD inhibition in immature rats is more pronounced, probably due to immaturity of the blood-brain barrier.
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PMID:Inhibition of glutamate decarboxylase activity by 3-mercaptopropionic acid has different time course in the immature and adult rat brains. 915 44

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

Endocrine and reproductive alterations are frequently reported to occur in women with temporal lobe epilepsy as well as in female rats in different experimental models of limbic seizures. As previously reported, women with epilepsy have lower fertility rates than women without epilepsy (Tanganelli, P., Regesta, G., 1992. Neurology (suppl.) 42 (5), 89-93; Cummings, L.N., Guidice, L., Morrel, M.J., 1995. Epilepsia 36, 355-359). In order to investigate the possible substrate of endocrine alterations in epilepsy, hormonal and gestational parameters were studied in female rats submitted to the pilocarpine model of epilepsy. The results demonstrated that the oestrus cycle is altered following pilocarpine-induced status epilepticus and such alteration lasted for several weeks. Progesterone, LH and FSH levels decreased and estradiol levels increased significantly during the period of spontaneous and recurrent seizures. The frequency of seizures during pregnancy and lactation decreased. These results document that significant changes in gonadal, hypophyseal and hypothalamic hormones, as well as in sexual behaviour, occur following status epilepticus induced by pilocarpine administration.
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PMID:Hormonal and gestational parameters in female rats submitted to the pilocarpine model of epilepsy. 976 26

Progesterone was administered percutaneously to postmenopausal women in topical applications on the breast and chest areas in a hydrophilic (gel), lipophilic and an emulsion type base. Venous blood samples were taken 2, 4, 6, 24, 48 and 72 h following administration. The plasma levels were evaluated by radioimmunoassay. Time of maximum concentration (tmax) was, in all cases, in the neighborhood of 4 h. Mean peak plasma concentrations were: 1 ng/ml for the lipophilic, 1.24 ng/ml for the hydrophilic and 2.26 ng/ml for the emulsion type base. The areas under the curves (AUCs) were practically equivalent for the first two methods, but higher values were obtained for administration in the emulsion type base. The elimination was slow, with a half-time varying in the range of 3040 h for all three types of base, a value that was much higher than those obtained after administration of progesterone via vaginal suppositories. The AUCs were parallel with the peak plasma concentrations: almost 2-fold higher for emulsion than for the gel and lipophilic base. Fit for plasma levels using mono-, bi- and tricompartmental models furnished acceptable results only in the case of monocompartmental model, which raises a number of physiological and physico-chemical considerations. A 'pseudomonocompartmental' model was constructed to explain this 'anomaly'.
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PMID:Pharmacokinetics of progesterone in postmenopausal women: 2. Pharmacokinetics following percutaneous administration. 984 83

Progesterone is an effective anticonvulsant against pentylenetetrazol (PTZ) seizures. This action is hypothesized to require the metabolic conversion of progesterone to the gamma-aminobutyric acidA receptor potentiating neuroactive steroid allopregnanolone by 5alpha-reductase isoenzymes followed by 3alpha-hydroxy oxidoreduction. We evaluated this possibility using the competitive 5alpha-reductase inhibitor finasteride. Progesterone (50-200 mg/kg, i.p.) protected mice against PTZ-induced seizures in a dose-dependent manner (ED50, 94 mg/kg). Pretreatment with finasteride (50-300 mg/kg, i.p.) produced a dose-dependent (ED50, 146 mg/kg) reversal of the protective effects of progesterone (2 x ED50 dose = 188 mg/kg). In contrast, finasteride (up to 300 mg/kg) failed to affect the anticonvulsant activity of allopregnanolone (10-30 mg/kg, i.p.; ED50, 12 mg/kg). Finasteride (up to 300 mg/kg) did not block the protective effect of high doses of progesterone (250-350 mg/kg) on tonic hindlimb extension in the maximal electroshock seizure test (progesterone ED50, 235 mg/kg). The anticonvulsant activity of progesterone against PTZ-induced seizures can be blocked by 5alpha-reductase inhibition, providing strong evidence that the anticonvulsant effect of the steroid in this model is mediated by its active metabolite allopregnanolone.
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PMID:Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice. 991 75

The temporolimbic structures of the brain that subserve emotional representation are highly epileptogenic and play an important role in the modulation of hormonal secretion and mediation of hormonal feedback. Estrogen is highly epileptogenic and exerts energizing and antidepressant effects. Excessive estrogen influence produces anxiety, agitation, irritability, and lability. It can promote the development of anxiety manifestations (e.g., panic, phobias, and obsessive-compulsive disorder). Progesterone and its metabolites inhibit kindling and seizure activity. They have potent anxiolytic effects, possibly by virtue of their GABAergic activity. Excessive progesterone influence produces sedation and depression. Testosterone has two major metabolites: estradiol, which can exacerbate seizures, and dihydrotestosterone, which blocks NMDA-type glutamate transmission and may be responsible for antiseizure effects. Testosterone has energizing effects and increases sexual desire in both men and women. In excess, however, it may promote aggressive, impulsive, and hypersexual behavior. Hormonal effects tend to be exaggerated or idiosyncratic in the setting of an abnormal or anomalous temporolimbic substrate, especially temporolimbic epilepsy. This may reflect altered neuronal responsivity to hormonal exposure perhaps by virtue of changes in the number of dendritic spines and receptors.
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PMID:Psychoneuroendocrine aspects of temporolimbic epilepsy. Part I. Brain, reproductive steroids, and emotions. 1010 Apr 30

The mechanism by which progesterone has its anti-seizure effects is unknown. Progesterone has a high affinity for intracellular progestin receptors, but has weak actions at gamma-aminobutyric acid (GABA)(A) receptors complexes. The progesterone metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) is devoid of activity at intracellular progestin receptors but is a highly effective modulator of GABA(A) receptor complexes. Whether progesterones anti-seizure actions are due to effects of progesterone itself or its metabolite 3alpha,5alpha-THP was investigated. In experiment 1, 25 ovariectomized Long-Evans rats were subcutaneously (s.c.) injected with 0.0, 4.0 or 8.0 mg/kg progesterone or 3alpha,5alpha-THP, 10 min prior to systemic administration of 32 mg/kg kainic acid. Four and 8.0 mg/kg progesterone significantly reduced the duration of partial and full seizures, without influencing the latency to partial or full seizures, or the number of partial or full seizures. 3alpha, 5alpha-THP (4.0 mg/kg) significantly increased the latency to initial partial seizure, and decreased the number and duration of partial seizures. In experiment 2, 60 ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats were s.c. injected with either progesterone (4.0 mg/kg, n = 12), 3alpha, 5alpha-THP (4.0 mg/kg, n = 13), progesterone (4.0 mg/kg)+4MA (10.0 mg of a 5alpha-reductase inhibitor, 17b-N, N-diethylcarbamoyl-4-methyl-4-aza,5alpha-androstan-3-one, n = 12), 4MA+vehicle (n = 10), or sesame oil vehicle (n = 13). Administration of progesterone or 3alpha, 5alpha-THP, but not vehicle control, P+4MA, or 4MA, resulted in significant decreases in partial seizures. In experiment 3, whole brain progesterone and 3alpha,5alpha-THP were measured by radioimmunoassay in additional rats (n = 66) administered the hormonal milieu indicated in experiments 1 and 2. Data suggest anti-seizure effects of progesterone may be due, in part, to metabolism to 3alpha,5alpha-THP and subsequent actions at GABA(A) receptor complexes.
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PMID:Anti-seizure effects of progesterone and 3alpha,5alpha-THP in kainic acid and perforant pathway models of epilepsy. 1072 16

The paper contains a review of reports concerned with how for hormones, epileptic seizures and antiepileptic drugs can be influenced by one another. Hormones influence brain excitability but, on the other hand, both epileptic seizures and antiepileptic drugs may alter hormone secretion and metabolism. Effect of hormones on seizures--Experimental studies revealed the properties which inhibit or stimulate convulsive reactivity of different hormones. Progesterone, testosterone, adrenocorticotropin and desoxycorticosterone are responsible for an increase in seizure threshold, while estradiol, cortisol and thyroid hormones cause a reduction. Effect of seizures on hormones--Epileptic seizures, chiefly tonic-clonic, also complex partial and sometimes simple partial seizures, result in "the hormonal storm". Immediately after an epileptic seizure, an increase is found in serum concentrations of prolactin, cortisol, adrenocorticotropin, triidothyronine, thyroxin, thyrotropin, luteotropin, follicular stimulating hormone and growth hormone. These changes may persist for two hours, while prolactin concentration even for 24 hours after a seizure. Effect of antiepileptic drugs on hormones--Antiepileptic drugs may affect hypothalamus-pituitary function directly or indirectly through neurotransmitter system. By induction of hepatic microsomal enzymes, some antiepileptic drugs cause acceleration of hormone metabolism, reducing hormone serum concentrations. Moreover, antiepileptic drugs enhance sex hormone binding globulin SHBG/synthesis, increase binding of these hormones and reduce their active fraction concentration in serum. Recognition of the relationship between epilepsy and hormonal system is necessary to obtain better understanding of this disease.
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PMID:[Epilepsy and hormones]. 1076 43

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