Renin-angiotensin system inhibitors potentiate the anticonvulsant activity of valproate in the mouse pilocarpine-induced seizures model

Systemic inhibition of the renin-angiotensin-aldosterone system (RAAS) has been recently suggested to participate in the regulation of seizures susceptibility. The purpose of the current study was to evaluate the effect of lisinopril and valsartan as RAAS modifiers on the protective action of the antiepileptic sodium valproate (VPA) against pilocarpine-induced convulsions in mice. Male albino mice were used in the study, and were grouped into five groups, viz., normal control group, seizures control group (seizures induced with pilocarpine), VPA-treated group and groups treated with combination of VPA with either lisinopril or valsartan. Lisinopril and valsartan were given orally for three (3) consecutive days including the day of seizure induction while VPA was injected in the three treatment groups 30 minutes before pilocarpine injection. All animals were observed for three (3) hours to assess the seizure severity and the latency to the onset of seizures. Death rate over the next twenty four (24) hours was recorded. Brain specimens from survivors were taken and examined pathologically. Treatment with either lisinopril or valsartan potentiated the effect of VPA in reducing the seizure severity, prolonged the onset of seizures, reduced the brain insult and decreased the mortality rate. Both agents did not influence plasma concentration of VPA excluding pharmacokinetic interactions. It is concluded that RAAS inhibition combined to VPA treatment may hold a potential for the cure of pathologies such as epilepsy.