Uric Acid Reduces Brain Damage and Improves the Benefits of rt-PA in a Rat Model of Thromboembolic Stroke

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Abstract
Uric acid is a natural antioxidant that protects the brain in a model of transient focal ischemia in rats. Here we sought to investigate whether uric acid was protective in a model of thromboembolic brain ischemia in rats, and whether the global benefit of recombinant tissue plasminogen activator (rt-PA) was improved by the combined treatment. Adult male Sprague-Dawley rats underwent either ischemia by thromboembolic middle cerebral artery occlusion (MCAO) or sham operation. Uric acid (16 mg/kg) was injected intravenously (i.v.). 20 mins after mCaO, whereas rt-PA (10 mg/kg) was administered i.v. at 3 h. A group of rats received the combined treatment. Rats underwent two neurologic examinations (30 mins and 24 h after MCAO). At 24 h, infarct volume was measured and brain neutrophil infiltration and protein tyrosine nitration were assessed. Treatment with either uric acid or rt-PA reduced infarct volume versus controls ( P < 0.05). The protective effect against brain ischemia was greater after cotreatment of uric acid with rt-PA ( P < 0.001), which added further benefit to rt-PA alone ( P < 0.05). The neurologic score worsened during the first 24 h in treatment controls, whereas it improved in rats receiving uric acid and/or rt-PA. Uric acid strongly reduced ischemia-induced tyrosine nitration, but it was more effective alone than combined with rt-PA, suggesting that reperfusion enhances nitrotyrosine formation. All treatments reduced postischemic brain neutrophil infiltration. These results show that uric acid administered early after thromboembolic stroke is neuroprotective in the rat brain, as it reduces infarct volume, ameliorates the neurologic function, attenuates the inflammatory response, and extends the benefits of rt-PA.