Attenuation of Ischemia-Reperfusion Injury in the Rat Neocortex by the Hydroxyl Radical Scavenger Nicaraven

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Abstract
Oxygen free radicals are considered important contributors to cerebral ischemia-reperfusion injury. The purpose of this study was to examine the effects of the hydroxyl radical scavenger, (+/-)-N, N'-propylenedinicotinamide (nicaraven), on cerebral injury after focal ischemia-reperfusion. A total of 58 male Sprague-Dawley rats was subjected to transient focal ischemia by occluding both carotid arteries and one middle cerebral artery for 3 hours. Animals received continuous infusions of doses of 20 mg/kg per hour or 60 mg/kg per hour of nicaraven beginning either 10 minutes before (pretreatment) or immediately after (posttreatment) ischemia. Infarction volumes were evaluated by staining coronal brain sections with 2% 2,3,5-triphenyltetrazolium chloride (n = 40). In other animals (n = 18), brain edema was evaluated 1 hour after ischemia. A dose of 20 mg/kg per hour of nicaraven elicited small reductions in infarction volume (14.7 and 12.3% for the pre- and posttreatment groups, respectively). Treatment with a dose of 60 mg/kg per hour of nicaraven provided significant reductions in the volume of infarction (18.6% [P < 0.05] and 20.9% [P < 0.01] reductions for the pre- and posttreatment groups, respectively). The reductions in infarction size did not differ significantly between the pre- and posttreatment groups receiving a dose of 60 mg/kg per hour of nicaraven. Posttreatment with either dose of nicaraven significantly reduced brain edema. This study demonstrates the neuroprotective effects of a hydroxyl radical scavenger when administered systemically during the reperfusion phase after transient focal ischemia. The results provide, to our knowledge, the first evidence that nicaraven is effective against ischemia-reperfusion injury in the brain and demonstrate that oxygen free radicals generated during reperfusion are important triggers of ischemic brain damage. Furthermore, the findings suggest that nicaraven may be a useful agent in limiting brain injury after ischemic stroke.

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