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Vol. 282, Issue 2, 543-553, 1997
Drug Development Group (M.G., S.R.G., J.M.W.), Preclinical
Pharmacology Laboratory, Addiction Research Center, National Institute
on Drug Abuse, National Institutes of Health, Baltimore, Maryland and
Department of Pharmacology (R.B.C.), CoCensys Inc., Irvine, California
Epilepsy continues to be a significant clinical problem as current
medications neither adequately control seizures nor are free of
untoward side-effects. Modulation of the neuroactive steroid site on
the 
-aminobutyric acid (GABA)A receptor complex may be an important new direction for pharmaceutical interventions in epilepsy. In this study we evaluated the protective actions of four neuroactive steroids, 3
-hydroxy-5-pregnan-20-one, the
3
-methylated analog, ganaxolone
(3-hydroxy-3-methyl-5-pregnan-20-one),
3-hydroxy-5-pregnan-20-one and Co 2-1068
(3-(4acetylphenyl)ethynyl-3,21-dihydroxy-5-20-one-21-hemisuccinate), against several standard convulsive tests in male, Swiss-Webster mice.
Consistent with their GABAergic actions, the neuroactive steroids as
well as diazepam and phenobarbital dose-dependently protected against
clonic convulsions induced by pentylenetetrazol; the
N-methyl-D-aspartate receptor antagonist, dizocilpine, was ineffective. In contrast to diazepam and phenobarbital, however, all of
the neuroactive steroids and dizocilpine produced full protection
against cocaine-induced convulsions. Some of the neuroactive steroids,
as well as dizocilpine, were efficacious against the seizures and
lethality induced by N-methyl-D-aspartate. Pregnenolone, a
steroid devoid of GABAergic activity, was not effective in any of the
convulsant models. Although all of the compounds produced motor
toxicity in high doses as measured by the inverted-screen test, the
neuroactive steroids demonstrated an equivalent or improved separation
between anticonvulsant potency and motoric impairment. Inactive doses
of the neuroactive steroids markedly enhanced the anticonvulsant
effects of diazepam against pentylenetetrazol without significantly
increasing motor toxicity. This adjunct treatment resulted in
protective indices ranging from 60 to 360 compared to 12 for diazepam
alone. The distinct profile of anticonvulsant activity of the
neuroactive steroids may be related to their combined actions on
-aminobutyric acid, N-methyl-D-aspartate receptors, or
voltage-operated Ca++ channels. These results
help to define the neuroactive steroids as a novel class of
antiepileptic agents and suggest their potential in clinical practice.
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