INHIBITION OF NEURONAL (TYPE-1) NITRIC-OXIDE SYNTHASE PREVENTS HYPEREMIA AND HIPPOCAMPAL-LESIONS RESULTING FROM KAINATE-INDUCED SEIZURES

The possible roles for nitric oxide produced by neurons in epileptic c onditions have been investigated from two different aspects: microcirc ulation and delayed damage. Our aim was to determine whether the selec tive inhibition of neuronal (type 1) nitric oxide synthase by 7-nitroi ndazole, during seizures induced by systemic kainate, modifies hippoca mpal blood flow and oxygen supply and influences the subsequent hippoc ampal damage. Experiments were performed in conscious Wistar rats whos e electroencephalogram was recorded. 7-Nitroindazole (25 mg/kg, i.p.) or its vehicle was injected 30 min before kainate administration (10 m g/kg, i.p.) and then twice at I-h intervals. Kainate triggered typical limbic seizures evolving into status epilepticus, identified by unint errupted electroencephalographic spike activity. The seizures were sto pped by diazepam (5 mg/kg, i.p.) after 1 h of status epilepticus. Thre e types of experiments were performed in vehicle-and 7-nitroindazole-t reated rats. (1) Hippocampal nitric oxide synthase activity was measur ed under basal conditions, at 1 h after the onset of the status epilep ticus and at 24 h after its termination (n=4-6 per group). (2) Hippoca mpal blood flow and tissue partial pressure of oxygen were measured si multaneously by mass spectrometry for the whole duration of the experi ment, while systemic variables and body temperature were monitored (n= 6 per group). (3) Hippocampal damage was revealed by Cresyl Violet sta ining and evaluated with a lesion score seven days after status epilep ticus (n=12 per group). Hippocampal nitric oxide synthase activity was not significantly modified during status epilepticus or the following day in vehicle-treated rats. In contrast, it was inhibited by 57% in 7-nitroindazole-treated rats, both in basal conditions and after 1 h o f status epilepticus, but was not different from its basal level 24 h later. 7-Nitroindazole significantly decreased basal hippocampal brood flow and tissue partial pressure in oxygen by 30% and 35%, respective ly without affecting any systemic or thermal variable. During status e pilepticus, 7-nitroindazole significantly reduced the increase in hipp ocampal blood how by 70% and prevented any increase in the tissue part ial pressure of oxygen. Seven days later, the hippocampal damage in th e CAI and CA3 layers was significantly less in 7-nitroindazole-treated rats than in vehicle-treated rats. These results indicate that the in hibition of neuronal nitric oxide synthase by 7-nitroindazole protects neurons from seizure-induced toxicity despite reducing blood flow and oxygen supply to the hippocampus. (C) 1998 IBRO. Published by Elsevie r Science Ltd.