Glia-derived steroids modulate epileptogenesis in a model of temporal lobe epilepsy

Purpose: The conversion of cholesterol into pregnenolone by cytochromeP450 cholesterol side-chain cleavage enzyme (P450 scc) is therate-limiting step in the steroid synthesis. Glial cells and neurons bothexpress P450 scc and synthesize neurosteroids, which are positive modulatorsof GABAergic transmission. Astrocytes become activated followingstatus epilepticus (SE), but it is presently unclear whether thisactivation leads to enhanced neurosteroidogenesis.Method: We studied the time course of P450 scc immunoreactivitychanges after pilocarpine-induced SE in adult (8 week-old) and young (3weeks-old) rats. To evaluate the role of P450 scc upregulation, we usedthe 5a-reductase inhibitor finasteride (100/kg s.c. for 3 weeks) to suppressthe synthesis of neurosteroids.Results: We demonstrated that P450 scc is upregulated in the CA3 hippocampalregion. Moreover the extent of P450 scc induction was directlyrelated to the onset of spontaneous recurrent seizures in adult (8-weekold)rats. In 3-week-old rats compared with adults, higher P450 scc levelsand a longer latent period were found. Interestingly, adult epileptic rats,treated with finasteride, compared with a group of vehicle-treated rats,presented anticipated generalized seizures (p<0.01). In young rats, finasterideanticipates seizures in approximately 50% of the animals.Conclusion: These findings suggest that neurosteroids can modulateepileptogenesis in the pilocarpine model of temporal lobe epilepsy.