Anticonvulsant effects of cyclosporin A on pentylenetetrazole-induced seizure and kindling: modulation by nitricoxidergic system

Abstract

Cyclosporin A (CsA) is known to decrease nitric oxide (NO) release in the nervous system. The present study was aimed at investigating the effects of acute administration of CsA on pentylenetetrazole (PTZ)-induced seizure threshold and latency and probable modulation of these effects by NO synthesis substrate l-arginine, and NO synthesis inhibitors N G-nitro- l-arginine methyl ester ( l-NAME) or aminoguanidine. Moreover, the effect of CsA per se or concomitant with l-arginine on the development of PTZ-induced kindling was assessed. CsA (0.05, 1, 5, 10 and 20 mg/kg, s.c.) dose-dependently increased PTZ-induced clonic seizure threshold and the latency for onset of myoclonic jerks, clonic seizures and clonic–tonic generalized seizures following PTZ administration. l-NAME (10 and 30 mg/kg, i.p.) but not aminoguanidine (50 and 100 mg/kg, i.p.) potentiated the anticonvulsant effects of CsA (1 and 10 mg/kg). l-arginine (60, 100 and 200 mg/kg, i.p.) inhibited the anticonvulsant effects of CsA (20 mg/kg) in a dose-related manner. The inhibitory effect of l-arginine on CsA-induced alterations of seizure threshold and latency was blocked by l-NAME but not with aminoguanidine. CsA (20 mg/kg) significantly inhibited the development of PTZ kindling and decreased the seizure intensity as tested by a challenge dose of PTZ. Pretreatment with l-arginine (60 mg/kg) reversed the inhibitory effects of CsA on kindling development. It was concluded that CsA exerts some anticonvulsant properties that may be due to its inhibition of nitric oxide synthesis.