Anticonvulsant effects of cyclosporin A on pentylenetetrazole-induced seizure and kindling: modulation by nitricoxidergic system.
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.
Homayoun
Houman
H
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Khavandgar
Simin
S
Dehpour
Ahmad Reza
AR
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000494:pharmacology; D003292:Convulsants; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007696:Kindling, Neurologic / Q000187:drug effects*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D000927:Anticonvulsants; D003292:Convulsants; D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D010433:Pentylenetetrazole