Involvement of NMDA Receptor and Nitric Oxide Pathway in the Anticonvulsant Effect of Genistein in Ovariectomized Mice

 Genistein is an isoflavonoid of soy that has been stated to show neuroprotection effect in some central nervous system disorders such as seizures and status epilepticus. from our previous study, we found that genistein showed an anticonvulsant effect through estrogenic and serotonergic receptors in Ovariectomized (OVX) mice. N-methyl d-aspartate (NMDA) receptors and Nitric Oxide (NO) pathway have been documented to be involved in genistein effects in rat’s hippocampus ischemic/reperfusion and Alzheimer’s disease.  Accordingly, we aimed to evaluate the possible involvement of NMDA receptors and nitrergic pathway in anticonvulsant effect of genistein on pentylenetetrazole (PTZ) induced seizures in OVX-mice.     NMRI female mice weighing 23-30 gr were undergone bilateral ovariectomy. Seizure susceptibility was studied by PTZ-induced seizures model after 14 days of recovery.  Genistein (10 mg/kg, i.p.) injection elevated the seizures threshold in OVX mice. The effect of a sub-effective dose of genistein (5 mg/kg, i.p.) was potentiated by L-NAME (nonspecific inhibitor of nitric oxide synthase (NOS); 10 mg/kg, i.p) and 7-nitroindazole (specific inhibitor of neural NOS; 25 mg/kg, i.p.), while, l-arginine (the nitric oxide precursor, 30 mg/kg, i.p) blocked the anticonvulsant activity of genistein (10 mg/kg). Acute injection of ketamine (0.5mg/kg, i.p.) and MK-801(0.05 mg/kg) as NMDA receptor antagonists before sub-effective dose of genistein (5 mg/kg, i.p.) showed a significant increase in seizure threshold among OVX mice.  In summary, our results demonstrated that NMDA receptors and neuronal nitric oxide synthase might be associated with an anticonvulsant effect of genistein after ovariectomy in mice.