Inhibitors of NO-synthase and donors of NO modulate kainic acid-induced damage in the rat hippocampus

The effects of nitric oxide synthase (NOS) inhibitors, N(omega)nitro-L-argi nine and 7-nitroindazole, and the NOS substrate L-arginine on kainic acid ( KA)-induced microglial reactivity and stress response were studied in the h ippocampus 7 and 1 days after KA, respectively. Density of peripheral-type benzodiazepine receptors was measured as an index of microglial reactivity. Histological damage in hippocampus was evaluated at 7 days by neuronal cou nting. KA increased the maximal number of binding sites (B-max) versus cont rols. Administration of either 7-nitroindazole (25 mg/kg) or N-omega-nitro- L-arginine (20 and 50 mg/kg) 24 hr before KA, further increased B-max. This later effect was abolished by L-arginine (1 g/kg), which given 24 hr befor e KA decreased B-max to control values. Also, KA-induced HSP72 stress respo nse was attenuated by pre-treatment with L-arginine. Histological evaluatio n showed reduced cell numbers in the pyramidal cell layer of the hippocampu s in groups receiving KA, either alone or in combination with 7-nitroindazo le. Administration of L-arginine before KA attenuated neuronal loss in CA3 but not CAI. A clear protective effect was observed, however, in CA1 and CA 3, in rats receiving both L-arginine plus 7-nitroindazole before KA. The re sults show that the combination of a NO substrate with a NOS inhibitor redu ces the neurotoxic effects of KA in the rat hippocampus. This study suggest s that extremely fine regulation of NO levels in the different neural cell types can modulate excitotoxicity. J. Neurosci. Res. 59: 797-805, 2000. (C) 2000 Wiley-Liss, Inc.