The Selective Inhibitor of Neuronal Nitric Oxide Synthase, 7-Nitroindazole, Reduces the Delayed Neuronal Damage Due to Forebrain Ischemia in Rats

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Abstract
Background and Purpose—The present study was designed to investigate whether neuronally derived nitric oxide (NO) plays a toxic role in the cascade of cellular events triggered by global cerebral ischemia in rats. Methods—7-Nitroindazole (7-NI) was used as a selective inhibitor of neuronal NO synthase. Global ischemia was induced for 20 minutes in anesthetized rats following the four-vessel occlusion model. Electroencephalogram and brain and body temperatures were continuously monitored. All rats were thermoregulated for the entire duration of anesthesia. 7-NI (25 mg/kg) or its vehicle was given intraperitoneally just after the carotid clamping and again 1 hour later. Rats were randomly divided into four groups: (1) vehicle (n=7); (2) 7-NI (n=7); (3) l-arginine (300 mg/kg IP)+7-NI (n=7); and (4) 7-NI associated with warming to 37°C for 7 hours after disruption of anesthesia to compensate for the decrease in temperature induced by 7-NI (n=9). Seven days after ischemia, hippocampal CA1 damage was evaluated by classic histology. The lesion was scored with the use of a point scale, and the surviving neurons were counted. Results—Lesion scores were significantly lower and neuron counts higher in the two (warmed and unwarmed) groups of rats in which 7-NI was given alone than in vehicle- and l-arginine+7-NI–treated rats. Conclusions—The results indicate that 7-NI was neuroprotective in 20-minute global ischemia in rats and that the neuroprotective effect of 7-NI was mostly due to the blockade of NO synthesis, suggesting that NO released from neurons in ischemic conditions has a deleterious influence on hippocampal pyramidal neurons.