Modulatory effects of nitric oxide-active drugs on the anticonvulsant activity of lamotrigine in an experimental model of partial complex epilepsy in the rat

Abstract

Background The effects induced by administering the anticonvulsant lamotrigine, the preferential inhibitor of neuronal nitric oxide synthase 7-nitroindazole and the precursor of NO synthesis L-arginine, alone or in combination, on an experimental model of partial complex seizures (maximal dentate gyrus activation) were studied in urethane anaesthetized rats. The epileptic activity of the dentate gyrus was obtained through the repetitive stimulation of the angular bundle and maximal dentate gyrus activation latency, duration and post-stimulus afterdischarge duration were evaluated. Results Either Lamotrigine (10 mg kg-1) or 7-nitroindazole (75 mg kg-1) i.p. administration had an anticonvulsant effect, significantly reducing the number of animals responding to angular bundle stimulation. On the contrary, i.p. injection of L-arginine (1 g kg-1) induced an aggravation of the epileptiform phenomena, demonstrated by the significant augmentation of the duration of both maximal dentate activation and afterdischarge. Furthermore, the injection of lamotrigine and 7-nitroindazole in combination significantly increased the anticonvulsant effects induced by the same drugs separately, either reducing the number of responding animals or decreasing both maximal dentate gyrus activation and afterdischarge durations. On the contrary, the combined treatment with L-arginine and lamotrigine did not modify the maximal dentate gyrus activation parameters suggesting an adversative effect of L-arginine-increased nitric oxide levels on the lamotrigine-induced anticonvulsant action. Conclusion The present results indicate that the nitrergic neurotransmission exerts a significant modulatory role in the control of the development of paroxystic phenomena in the maximal dentate gyrus activation model of epilepsy. Finally, our data suggest a functional relationship between the nitric oxide system and the anticonvulsant effect of lamotrigine which could be enhanced by reducing nitric oxide levels and, conversely, dampened by an increased nitrergic activity.