Cyclosporine A-increased nitric oxide production in the rat dorsal hippocampus mediates convulsions

Abstract

To test whether nitric oxide (NO) participates in cyclosporine A (CsA)-induced neurotoxicity including convulsions, we examined the effect of an NO synthase inhibitor on convulsions induced by combined treatment with CsA and bicuculline in mice and the effect of CsA on NO production in the dorsal hippocampus using an in vivo microdialysis method in rats. CsA (200 mg/kg, i.p.) significantly increased the intensity of convulsions induced by an intracerebroventricular injection of bicuculline (25 pmol) in mice. This facilitation was blocked by N ω-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, but not by N ω-nitro-D-arginine methyl ester (D-NAME), an inactive form of L-NAME (10 mg/kg, i.p.). CsA (20–50 mg/kg, i.p.) dose-dependently increased NO 2 - levels in dialysates obtained with microdialysis in the rat dorsal hippocampus. This enhanced NO 2 - formation was blocked by L-NAME but not by D-NAME (50 mg/kg, i.p.). These findings suggest that CsA stimulates NO production and induces convulsions as a result of an interaction between NO and the γ-aminobutyric acid (GABA) system in the hippocampus.