Abstracts

Temporal lobe epilepsy (TLE) is one of the most common forms of intractable epilepsy. Despite the availability of over twenty-five antiepileptic drugs, nearly 30% of people with epilepsy have intractable seizures. TLE is characterized by a latent period between the initial injury and the onset of spontaneous recurrent seizures (SRS) and a chronic epileptic state. These characteristics are expressed in pilocarpine-treated rats, an animal model of TLE. Neurosteroids are endogenous modulators of seizure susceptibility and hence could provide novel insights for the treatment of epilepsy. Allopregnanolone is a neurosteroid synthesized in the brain, but the therapeutic potential of this steroid remains unclear. In this study, we used the rat with pilocarpine-induced epilepsy as an animal model of TLE. We tested the hypothesis that endogenous GABAergic neurosteroids inhibits the frequency and severity of spontaneous seizures and electrographic discharges in pilocarpine-induced epileptic rats. We recently characterized the pilocarpine model of TLE, including the occurrence of SRS. We adapted the lithium-pilocarpine protocol described by Loescher for induction of chronic epilepsy. Female rats were subjected to pilocarpine-induced status epilepticus (SE) by multiple injections (10 mg/kg, i.p., per 30 min). Rats were monitored for SRS during 6-10 weeks post pilocarpine. Behavioral and EEG seizures were recorded throughout this period. Occurrence of SRS was monitored for 8 h/day in all rats. Antiepileptic effects of allopregnanolone were investigated in chronic epileptic rats. Allopregnanolone (2-10 mg/kg) was injected thrice daily for 5 days for two weeks and animals were monitored for spontaneous seizures. Repeated administration of pilocarpine resulted in persistent SE after 2-3 injections. Rats developed SRS after a latency of 35-50 days after pilocarpine treatment. The average seizure frequency was 4 seizures per 5 days. However, there was no tendency of increased frequency of SRS during the chronic period. To verify the occurrence of spontaneous seizures, we recorded EEG from two distinct areas (hippocampus and cortex) in pilocarpine-treated rats. Generally, the epileptiform discharges and paroxysms were well correlated with behavioral motor seizures. Rats showed variable intermittent spikes and burst of spikes. In allopregnanolone-treated rats, the frequency of SRS was dramatically reduced as well as the intensity of electrographic activity as compared with predrug and postdrug control period. In conclusion, the GABAergic neurosteroid allopregnanolone exhibited efficacy against spontaneous seizures in the rat pilocarpine model of chronic epilepsy. Pilocarpine model was selected because it replicates several clinical features of human TLE and allows testing new drugs on the frequency and severity of spontaneous seizures.