Anticonvulsant effects of 7-nitroindazole in rodents with reflex epilepsy may result from L-arginine accumulation or a reduction in nitric oxide or L-citrulline formation

Abstract

1. To investigate the role of nitric oxide in epilepsy we have studied the effects of agents which affect nitric oxide synthesis in sound-induced seizures in DBA/2 mice and in genetically epilepsy-prone (GEP) rats. 2. The neuronal selective nitric oxide synthase inhibitor, 7-nitroindazole (7-NI) is anticonvulsant in these models with ED50 values against clonic seizures in mg kg-1 i.p. (times following injection) of: 74 (+ 0.25 h), 120 (+ 1.h) in DBA/2 mice, and 56 (+ 0.25 h), 42 (+ 0.5 h), 36 (+ 1.h), 28 (+ 2.h), 38 (+ 4 h), 93 (+ 8 h) in GEP rats. 3. Therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) for 7-NI are low, ranging from 0.6 to 1.1 at + 0.25 h to + 1.h after administration in GEP rats, but are more favourable at later times (1.6 at + 2.h and 2.9 at + 4 h). 4. The substrate for nitric oxide synthase, L-arginine (500-5000 mg kg-1, i.p. or 100-300 μg, i.c.v.) but not D-arginine (300 μg i.c.v.) is anticonvulsant in DBA/2 mice. L-Arginine (500-5000 mg kg-1, i.p. or 1800-6000 μg, i.c.v.) is a more potent anticonvulsant than D-arginine (1500-2500 mg kg-1, i.p. or 6000 μg, i.c.v.) in GEP rats. 5. In DBA/2 mice, L-arginine (30 μg i.c.v.) reverses the anticonvulsant effect of 7-NI (50 mg kg-1, i.p.). 6. In GEP rats, low dose L-arginine (25-50 mg kg-1, i.p.) but not D-arginine (50 mg kg-1, i.p.) reverses the anticonvulsant effect of low dose 7-NI (25 mg kg-1, i.p.). A higher dose of L-arginine (500 mg kg-1, i.p.) or 7-NI (50 mg kg-1, i.p.) produces summation of anticonvulsant effect. 7. The product for nitric oxide synthase, L-citrulline (250-831 μg i.c.v.), is convulsant in DBA/2 mice. 8. The anticonvulsant effect of the neuronal selective nitric oxide synthase inhibitor, 7-nitroindazole, may therefore be mediated by L-arginine accumulation, as well as by a reduction in nitric oxide and L-citrulline formation in rodent models of reflex epilepsy.