Demonstrating the dose- and time-related effects of 7-nitroindazole on picrotoxin-induced convulsions, memory formation, brain nitric oxide synthase activity, and nitric oxide concentration in rats

Abstract

In this study, the dose (50, 100, 150, and 200 mg/kg)- and time (30 and 60 min)- related effects of 7-nitroindazole (7-NI), a neuronal specific inhibitor of nitric oxide synthase (NOS) were tested on picrotoxin (5 mg/kg)-induced convulsions and memory formation in rats. The changes produced by these doses of 7-NI were determined on NOS activity and nitric oxide (NO) concentration in the brain. The effects of 7-NI were tested in animals pretreated (30 min) with L-arginine (500 and 1000 mg/kg). 7-NI, at 50 and 100 mg/kg, did not produce significant changes in NOS activity and NO concentration in the brain and memory formation. However, the convulsant action of picrotoxin was inhibited in a dose-dependent manner in these animals. A time-dependent decrease in the activity of NOS and the concentration of NO, a promotion of picrotoxin-induced convulsions, and an impairment of memory were found in animals treated with 150 and 200 mg/kg of 7-NI. The larger and not the smaller dose of L-arginine raised the concentration of NO, inhibited picrotoxin-induced convulsions and promoted memory process. Either dose of L-arginine failed to prevent 50 and 100 mg/kg of 7-NI from inhibiting convulsions. The effects of the larger doses of 7-NI (150 and 200 mg/kg) were effectively prevented by the increase of NO and not the ineffective dose of L-arginine. These results suggest that 7-NI (50 and 100 mg/kg) decreases convulsions by a nonspecific mechanism and that an inhibition of NOS by the larger doses of it (150 and 200 mg/kg) results in proconvulsant action and memory impairment. The data further show that the margin between the protective and proconvulsant doses of 7-NI is relatively narrow. These results have been taken together with the earlier reports that 7-NI produces learning impairment and fails to increase the anticonvulsant effect of traditional antiepileptic agents on experimentally induced convulsions to conclude that 7-NI can never emerge as an anticonvulsant agent for clinical use.