Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice

Abstract

Several structurally related metabolites of progesterone (3α-hydroxy pregnane-20-ones) and deoxycorticosterone (3α-hydroxy pregnane-21-diol-20-ones) and their 3β-epimers were evaluated for protective activity against pilocarpine-, kainic acid- and N-methyl-D-aspartate (NMDA)-induced seizures in mice. Steroids with the 3-hydroxy group in the α-position and 5-H in the α- or β-configurations were highly effective in protecting against pilocarpine (416 mg/kg, s.c.)-induced limbic motor seizures and status epilepticus (ED 50 values, 7.0–18.7 mg/kg, i.p.). The corresponding epimers with the 3-hydroxy group in the β-position were also effective but less potent (ED 50 values, 33.8-63.5, i.p.). Although the neuroactive steroids were considerably less potent than the benzodiazepine clonazepam in protecting against pilocarpine seizures, steroids with the 5α,3α-configuration had comparable or higher protective index values (TD 50 for motor impairment -4- ED 50 for seizure protection) than clonazepam, indicating that some neuroactive steroids may have lower relative toxicity. Steroids with the 5α,3α- or 5β,3α-configurations also produced a dose-dependent delay in the onset of limbic seizures induced by kainic acid (32 mg/kg, s.c.), but did not completely protect against the seizures. However, when a second dose of the steroid was administered 1 hr after the first dose, complete protection from the kainic acid-induced limbic seizures and status epilepticus was obtained. The steroids also caused a dose-dependent delay in NMDA (257 mg/kg, s.c.)-induced lethality, but did not completely protect against NMDA seizures or lethality. We conclude that neuroactive steroids are highly effective in protecting against pilocarpine- and kainic acid-induced seizures and status epilepticus in mice, and may be of utility in the treatment of some forms of status epilepticus in humans. Published by Elsevier Science Ltd.