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

The conversion of cholesterol intopregnenolone by the enzyme cholesterolside-chain cleavage cytochromeP450 (P450scc) is the rate-limitingstep in the steroid synthesis. Glialcells and neurons both expressP450scc and synthesize neurosteroidsthat act as positive modulators ofGABAergic transmission. Astrocytesbecome activated following statusepilepticus (SE), but it is presently unclearwhether this activation leads toenhanced neurosteroid synthesis. Westudied the time course of P450sccimmunoreactivity changes afterpilocarpine-induced SE and its relationshipwith epileptogenesis. Wefound that P450scc is upregulated inthe CA3 hippocampal region, afterSE. Induction of P450scc was mainlyobserved in astrocytes identified by aGFAP antibody, although hemeoxygenase-1-positive microglial cells,RIP-positive oligodendrocytes andNeuN-neurons were also stained forP450scc (Fig. 1). The extent ofP450scc induction was directly relatedwith the onset of spontaneouslyrecurrent seizures in adult (8-weekold)rats. In addition, in young (3-week-old) rats the induction ofP450scc and the latent period durationwere much larger than in adultrats. To further evaluate the role ofP450scc upregulation, we used the5-reductase inhibitor finasteride(100 mg/kg/day for approximately 3weeks) to suppress the synthesis ofGABA-modulating neurosteroidssuch as allopregnanolone. Interestingly,adult epileptic rats, comparedwith a group of vehicle-treated ratsthat experienced a similar SE, presentedwith significantly (p<0.01) anticipatedgeneralized seizures whentreated with finasteride. In young rats,we observed early generalized seizuresin approximately 50% of the animals.These findings suggest thatneurosteroids can modulate epileptogenesisin the pilocarpine modelof temporal lobe epilepsy.