Neurosteroids and epileptogenesis in the pilocarpine model: evidence for a relationship between P450scc induction and length of the latent period

Purpose: Cytochrome P450 cholesterol side-chaincleavage enzyme (P450scc) catalyzes the initialstep in the biosynthesis of neurosteroids withinthe brain. We sought to determine which cellsexpress P450cc and whether neurosteroids play arole in the regulation of epileptogenesis followingpilocarpine-induced status epilepticus (SE).Methods: Rats experienced uninterrupted SE orSE terminated with diazepam at 60, 120, and180 min. P450scc induction in CA3 hippocampuswas determined by double immunolabeling withP450scc antiserum and monoclonal antibodiesagainst GFAP (astrocytes), RIP (oligodendrocytes),or heme oxygenase-1 (microglia).Results: SE was associated with P450scc inductionin many astrocytes and a small number of microgliaand oligodendrocytes in the hippocampal CA3strata radiatum and lacunosum-moleculare. Theextent of P450scc induction increased withincreasing SE duration. Paradoxically, increasedP450scc induction in rats experiencing SE for180 min or more was associated with the delayedonset of spontaneous recurrent seizures. Treatmentwith the 5a-reductase inhibitor finasteride(100 mg/kg/day for 25 days), which inhibits thesynthesis of c-aminobutyric acid (GABA)A receptormodulating neurosteroids such as allopregnanolone,was associated with a significantreduction in time to the onset of spontaneous seizuresin rats exposed to 180-min but not 90-minSE.Discussion: P450scc is induced by SE in a diversepopulation of hippocampal glia. Induction ofP450scc is associated with the delayed onsetof spontaneous seizures. Conversely, inhibitionof neurosteroid synthesis accelerated the onset ofspontaneous seizures, but only in animals exhibitingsignificant increases in P450scc. These findingssuggest that induction of neurosteroid synthesis inreactive glial cells is associated with delayed onsetof spontaneously recurrent seizures.