The selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reduces the delayed neuronal damage due to forebrain ischemia in rats.
OBJECTIVE
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 degrees 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.
Nanri
K
K
Laboratoire de Recherches Cérébrovasculaires, CNRS UPR 640, IFR6, Université Paris 7, France.
Montécot
C
C
Springhetti
V
V
Seylaz
J
J
Pinard
E
E
D000818:Animals; D001831:Body Temperature; D002452:Cell Count; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology; D007191:Indazoles / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D016548:Prosencephalon / Q000098:blood supply* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D007191:Indazoles; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C080122:7-nitroindazole