In vivo study of the effect of valpromide and valnoctamide in the pilocarpine rat model of focal epilepsy

Purpose. We evaluated the effectiveness of the commonly used antiepileptic drug sodium valproate (400 mg/kg) and two of its amide derivatives, valprom ide and valnoctamide (both 100 mg/kg), in an in vivo rat model of focal epi lepsy. Our main interest was to get insight into possible changes in extrac ellular amino acid neurotransmitter levels following administration of the drugs, both in control and in epileptic conditions. Methods: Seizures were evoked in freely moving rats by intrahippocampal adm inistration of pilocarpine via a microdialysis probe (10 mM for 40 min at 2 mul/min). Microdialysis was also used as bl vivo sampling technique and al terations in extracellular hippocampal glutamate and GABA levels were monit ored. Electrophysiological evidence for the presence or absence of seizures was simultaneously recorded with electrocorticography. Results. The focally evoked pilocarpine-induced seizures were completely pr evented by acute intraperitoneal pretreatment with each of the three drugs in the respective doses. Effective protection was reflected in the electroc orticographic recordings and in the lack of sustained elevations of the ext racellular glutamate levels after pilocarpine perfusion. Little effects wer e seen on the basal extracellular amino acid levels after systemic administ ration of each of the compounds, nor after the intrahippocampal administrat ion of sodium valproate. Conclusions. Valnoctamide and valpromide (100 mg/kg) proved to be at least as effective as their parent compound sodium valproate (400 mg/kg) against pilocarpine-induced seizures. All three compounds however failed to induce significant initial alterations in extracellular hippocampal GABA release. This questions the enhance ment of GABA-mediated inhibition as bring one of their mechanisms of action.