Effects of Nitric Oxide on Reactive Oxygen Species Production and Infarction Size after Brain Reperfusion Injury

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Abstract
Deleterious effects of strokes may be ameliorated when thrombolysis (i.e., with recombinant tissue plasminogen activator) restores circulation. However, reperfusion injury, mediated by oxygen free radicals (reactive oxygen species [ROS]), may limit the benefits of recombinant tissue plasminogen activator treatment. We hypothesized that, during reperfusion, exogenous nitric oxide (NO) would reduce stroke size by quenching ROS. To investigate this hypothesis, we used two in vivo ischemia-reperfusion models, i.e., autologous cerebral embolism in rabbits and filament middle cerebral artery occlusion in rats. Using these models, we measured ROS levels (rabbit model) and stroke volumes (rat model) in response to transient ischemia, with and without intracarotid administration of ultrafast NO donor proline NO (proliNO). In the rabbit cerebral embolism model, intracarotid administration of proliNO (10−6 mol/L) (n = 6) during reperfusion decreased free radical levels from 538 ± 86 nmol/L in the vehicle-treated group (n = 7) to 186 ± 31 nmol/L (2,3′-dihydroxybenzoic acid; P < 0.001) and from 521 ± 86 nmol/L (n = 7) to 201 ± 39 nmol/L (2,5′-dihydroxybenzoic acid; P < 0.002). In the rat middle cerebral artery occlusion model, intracarotid administration of proliNO (10−5 mol/L) (n = 10) during reperfusion reduced the brain infarction volume from 256 ± 48 mm3 in the vehicle-treated group (n = 8) to 187 ± 41 mm3 (P < 0.005). In both experimental groups, intracarotid infusion of proliNO did not affect regional cerebral blood flow, mean arterial blood pressure, or brain and body temperatures. The beneficial effects of early restoration of cerebral circulation after cerebral ischemia were enhanced by intracarotid infusion of proliNO, most likely because of ROS scavenging by NO. These findings suggest the possibility of preventive treatment of reperfusion injury using NO donors.

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