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)

Stress affects seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, we provide evidence that GABA(A) receptor-modulating neurosteroids derived from deoxycorticosterone (DOC) play a role in stress-related changes in seizure control. DOC, an adrenal steroid whose synthesis is enhanced during stress, undergoes sequential metabolic reduction by 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase to form 5alpha-dihydrodeoxycorticosterone (DHDOC) and allotetrahydrodeoxycorticosterone (THDOC), a GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Acute swim stress in rats significantly elevated plasma THDOC concentrations and raised the pentylenetetrazol (PTZ) seizure threshold. Small systemic doses of DOC produced comparable increases in THDOC and PTZ seizure threshold. Pretreatment with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of DOC to DHDOC, reversed the antiseizure effects of stress. DOC also elevated plasma THDOC levels and protected mice against PTZ, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, picrotoxin, and amygdala-kindled seizures in mice (ED50 values, 84-97 mg/kg). Finasteride reversed the antiseizure activity of DOC (ED50, 7.2 mg/kg); partial antagonism was also obtained with indomethacin (100 mg/kg), an inhibitor of 3alpha-hydroxysteroid oxidoreductase. Finasteride had no effect on seizure protection by DHDOC and THDOC, whereas indomethacin partially reversed DHDOC but not THDOC. DHDOC, like THDOC, potentiated GABA-activated Cl- currents in cultured hippocampal neurons (< or =1 microm) and directly activated GABA(A) receptor currents (> or =1 microm), compatible with a role for DHDOC in the antiseizure activity of DOC. DOC is a mediator of the physiological effects of acute stress that could contribute to stress-induced changes in seizure susceptibility through its conversion to neurosteroids with modulatory actions on GABA(A) receptors including THDOC and possibly also DHDOC.
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PMID:Stress-induced deoxycorticosterone-derived neurosteroids modulate GABA(A) receptor function and seizure susceptibility. 1197 55

Allopregnanolone (ALLO, 3alpha,5alpha-tetrahydroprogesterone), a positive allosteric modulator of actions of gamma-aminobutyric acid GABA) at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: a type I 5alpha-reductase and a 3alpha-hydroxysteroid oxidoreductase. We previously demonstrated that long-term social isolation of mice caused a significant decrease in brain ALLO content via suppression of type I 5alpha-reductase and its mRNA expression. In this study, to clarify a physiological role of endogenous brain ALLO, we investigated changes in seizure susceptibility of mice following protracted social isolation and compared with those of mice treated with SKF105111 (SKF), an inhibitor of types I and II 5alpha-reductase. Social isolation of mice for 7 weeks prior to the experiments caused a significant increase of seizure susceptibility to the GABA(A) receptor antagonist picrotoxin but not to the glycine receptor antagonist strychnine or the glutamate receptor agonist kainic acid. The change in the seizure susceptibility was completely reversed by 2.5 mg/kg ip ALLO, a dose that per se had no effect on picrotoxin-induced seizure. Treatment of mice with SKF (20 mg/kg ip) also reduced a threshold dose of picrotoxin, but not that of strychnine or kainic acid, which was required to elicit seizure in group-housed mice. The effect of SKF was attenuated by ALLO (2.5 mg/kg ip). In contrast, SKF treatment had no effect on picrotoxin-induced seizure in socially isolated mice. These findings suggest that endogenous brain ALLO plays a suppressive role in seizure susceptibility via a positive modulation of GABA(A) receptor function and that social isolation enhances seizure susceptibility in mice via reduction of GABA(A) receptor function caused by a decrease of endogenous ALLO.
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PMID:Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems. 1295 25