ANTICONVULSANT AND BEHAVIORAL-EFFECTS OF NEUROACTIVE STEROIDS ALONE AND IN CONJUNCTION WITH DIAZEPAM

Epilepsy continues to be a significant clinical problem as current med ications neither adequately control seizures nor are free of untoward side-effects. Modulation of the neuroactive steroid site on the gamma- aminobutyric acid (GABA)(A) receptor complex may be an important new d irection for pharmaceutical interventions in epilepsy. In this study w e evaluated the protective actions of four neuroactive steroids, 3 alp ha-hydroxy-5 alpha-pregnan-20-one, the 3 beta-methylated analog, ganax olone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one), 3 alpha- hydroxy-5 beta-pregnan-20-one and Co 2-1068 (3 beta-(4acetylphenyl)eth ynyl-3 alpha,21-dihydroxy-5 beta-20-one-21-hemisuccinate), against sev eral standard convulsive tests in male, Swiss-Webster mice. Consistent with their GABAergic actions, the neuroactive steroids as well as dia zepam and phenobarbital dose-dependently protected against clonic conv ulsions induced by pentylenetetrazol; the N-methyl-D-aspartate recepto r antagonist, dizocilipine, was ineffective. In contrast to diazepam a nd phenobarbital, however, all of the neuroactive steroids and dizocli pine produced full protection against cocaine-induced convulsions. Som e of the neuroactive steroids, as well as dizocilpine, were efficaciou s against the seizures and lethality induced by N-methyl-D-aspartate. Pregnenolone, a steroid devoid of GABAergic activity, was not effectiv e in any of the convulsant models. Although all of the compounds produ ced motor toxicity in high doses as measured by the inverted-screen te st, the neuroactive steroids demonstrated an equivalent or improved se paration between anticonvulsant potency and motoric impairment. Inacti ve doses of the neuroactive steroids markedly enhanced the anticonvuls ant effects of diazepam against pentylenetetrazol without significantl y increasing motor toxicity. This adjunct treatment resulted in protec tive indices ranging from 60 to 360 compared to 12 for diazepam alone. The distinct profile of anticonvulsant activity of the neuroactive st eroids may be related to their combined actions on gamma-aminobutyric acid, N-methyl-D-aspartate receptors, or voltage-operated Ca++ channel s. These results help to define the neuroactive steroids as a novel cl ass of antiepileptic agents and suggest their potential in clinical pr actice.