Lisinopril potentiates the anticonvulsant activity of valproate in the mouse pilocarpine-induced seizures model

R Hegazy1, A Mahdy2. 1National Research Center, Department of Pharmacology/ Postcode: 12622, Egypt, 2Dubai Pharmacy College, Department of Pharmacology & Therapeutics/ Postcode: 19099, United Arab Emirates

Epilepsy is a neurological disorder characterized by recurrent seizures that affects about 1% of people worldwide. During the past decades, some mechanisms involved in generation of seizures have been identified and, to some extent, partially understood. Lisinopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well-known antihypertensive drug. Besides the effect on the peripheral renin-angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizures susceptibility. The purpose of the current study was to evaluate the effect of lisinopril on the protective action of the antiepileptic sodium valproate against pilocarpine-induced convulsions in mice. Male albino mice weighing 20-25 g were grouped into four groups each consisting of 15 animals. One group was intraperitoneally injected with saline and served as normal control group. Group 2 received pilocarpine (300 mg/kg, i.p.) and served as seizures control group. Groups 3 and 4 were respectively treated with sodium valproate (250 mg/kg, i.p.) alone and in combination with lisinopril (20 mg/kg, i.p.) 30 minutes before the induction of convulsions by pilocarpine. All animals were observed for 2 hours following pilocarpine injection. Seizures were assessed in terms of a composite seizure severity score (SSS). Latency to the onset of seizures and the death rate over 24 hours were recorded. Chi-square test or one-way ANOVA with Tukey’s post-test were used for statistical analysis as appropriate, and p < 0.05 was considered significant. It was found that combination of lisinopril with valproate shifted 20% of the animals tested from the high to the moderate and low SSS compared to valproate alone–treated group. The mortality rate was as high as 52.6% in the animals receiving pilocarpine alone. This rate was reduced to 20 and 30% in animals treated with valproate and valproate/lisinopril combination, respectively. The onset of seizure in minutes was significantly increased in the combination group (14.4 + 4.7) as compared to valproate alone–treated group (5.8 + 1.9). These results suggest that lisinopril may hold a potential for the treatment of pathologies such as epilepsy, and its enhancement of the protective effect of valproate in the pilocarpine-induced seizures in mice implicates a possible therapeutic relevance of such drug combination.