The possible role of nitric oxide signaling and NMDA receptors in allopurinol effect on maximal electroshock- and pentylenetetrazol-induced seizures in mice

Abstract

Allopurinol, a uric-acid-lowering medication, has shown its efficacy in several studies suggesting that allopurinol can be prescribed as adjunctive cure meant for intractable epilepsy. The exact mechanism of allopurinol is still unknown. This study evaluates allopurinol’s effect on seizure threshold, seizure incidence, and mortality rate in mice models. Moreover, the possible involvement of nitric oxide (NO) pathway and N-methyl-D-aspartate (NMDA) receptors are investigated.To evaluate the effect of allopurinol on seizure, we used the pentylenetetrazole (PTZ)-induced seizure along with maximal electroshock (MES)-induced seizure. To assess the underlying mechanism behind the allopurinol activity, we used nitric oxide synthase (NOS) substrate (L-arginine), NOS inhibitors (L-NAME, aminoguanidine, 7-nitroindazole), and NMDA receptor antagonist (MK-801).Intraperitoneal allopurinol administration at a dose of 50 mg/kg in mice showed a significant (p < 0.001) anti-convulsant activity in the PTZ-induced seizure. Even though pre-treatment with L-Arginine (60 mg/kg) potentiates allopurinol’s anti-convulsant effect in the PTZ-induced seizure, pre-treatment with L-NAME (10 mg/kg), aminoguanidine (100 mg/kg), and 7-nitroindazole (30 mg/kg) reversed the anti-convulsant effect of allopurinol in the PTZ-induced seizure. In addition, pre-treatment with MK-801 also decreased the anti-convulsant effect of allopurinol in the PTZ-induced seizure. While allopurinol at a dose of 50 mg/kg and 100 mg/kg did not induce protection against seizure incidence in the MES-induced seizure, it revealed a remarkable effect in reducing the mortality rate in the MES-induced seizure.Allopurinol increases the seizure threshold in PTZ-induced seizure and enhances the survival rate in MES-induced seizure. Allopurinol exerts its anti-convulsant effect, possibly through targeting NO pathway and NMDA receptors.