Effects of chronic treatment with levetiracetam on hippocampal field responses after pilocarpine-induced status epilepticus in rats

摘要

Levetiracetam (Keppm~R) is a new generation antiepileptic drug characterized by a unique profile of activity in experimental models of epilepsy. It also has a distinct binding site in the brain, i.e. the synaptic vesicle protein type 2 (SV2A). Levetiracetam has been reported to have antiepileptogenic and disease-modifying properties. In the present study the effects of chronic treatment with levetiracetam were assessed in rats that sustained pilocarpine-induced status epilepticus (SE). Hippocampal field potentials were recorded in vivo in anesthetized animals after 3-day washout period that followed 21 -day treatment with different doses of levetiracetam (50,150 or 300 mg/kg/day) administered via ALZET~R osmotic mini-pumps. Vehicle treated rats together with naive animals (not subjected to SE) were used as control groups. Chronic treatment with levetiracetam yielded clinically relevant plasma concentrations throughout the experiment with complete washout of the drug 3 days after treatment cessation. At this point in time post-SE rats chronically treated with vehicle developed clear signs of hippocampal hyperexcitability, i.e. increased amplitude of population spike (PS) recorded in the dentate gyrus and reduced paired-pulse inhibition in the CA1 area. Levetiracetam treatment dose-dependently counteracted these long-term effects of pilocarpine-induced SE. Furthermore, at the dose of 300 mg/kg/day levetiracetam restored these parameters back to control level. The present results indicate that chronic treatment with levetiracetam completely inhibits the development of hippocampal hyperexcitability following pilocarpine-induced SE.