Effects of enalapril and losartan alone and in combination with sodium valproate on seizures, memory, and cardiac changes in rats.

PURPOSE: Cardiac changes accompanying seizures may be responsible for sudden unexpected death in epilepsy (SUDEP), and drugs with antiseizure and favorable cardiovascular profile could be beneficial. The effect of losartan and enalapril alone and in combination with sodium valproate on seizures, cognition, cardiac histopathology, and serum brain-derived neurotropic factor (BDNF) levels were determined.

METHODS

Male "Wistar" rats (200-250 g) were administered enalapril (20 mg/kg, intraperitoneally (i.p.)) and losartan (10 mg/kg, i.p.) daily and simultaneously subjected to pentylenetetrazole (PTZ)-kindling (PTZ 30 mg/kg, i.p., every alternate day). Enalapril and losartan were injected 45 & 120 min before seizure stimuli. In another set of experiments, sodium valproate (150 mg/kg, i.p.) alone or in combination with enalapril (20 mg/kg, i.p.) and losartan (10 mg/kg, i.p.) were administered daily during induction of kindling. The effect on seizures and behavior were noted; rats were sacrificed, and blood and hearts were collected for further analysis, i.e., BDNF levels, heart weight-body weight (HWBW) ratio, and cardiac histopathology.

RESULTS

Losartan, but not enalapril, suppressed the seizure score in PTZ kindling. Sodium valproate alone or in combination with losartan or enalapril prevented kindled seizures. Sodium valproate per se caused cognitive impairment, which was prevented on combining with losartan or enalapril. A decrease in HWBW ratio was observed only in enalapril group (p value = 0.02). Kindling led to cardiac ischemic changes, which could be prevented by losartan and sodium valproate. Serum BDNF level was decreased in PTZ (p value = 0.02) and sodium valproate per se group (p value = 0.04), but sodium valproate could reverse the PTZ-induced decrease in serum BDNF level.

CONCLUSION

The use of losartan with sodium valproate in epilepsy may prevent the cognitive and cardiac sequelae of seizures. The BDNF levels as a marker for cardiovascular risk in persons with epilepsy (PWE) needs to be explored further.