Curcumin, a natural polyphenol compound which is contained in turmeric (Curcuma longa), has been reported to protect against cerebral ischemia-reperfusion injury in experimental animals. In the present study, we investigated the effects of CUD003, a novel synthetic derivate of curcumin, and the possible mechanism of its action against ischemic brain damage induced by middle cerebral artery occlusion following reperfusion (MCAO/Re) in rats. Male Sprague-Dawley rats were subjected to 2h of MCAO, followed by reperfusion for 24h. CUD003 (100 mg/kg) was administered intraperitoneally 110 min before reperfusion. In vehicle-treated control rats, lesions in the ipsilateral cerebral cortex and subcortical tissues (infarct volume: 34.5±2.3%) and a severe neurological deficit (score: 8.9±1.0) were observed. Treatment with CUD003 significantly decreased the infarct volume (16.3±2.8%), which was accompanied with an improvement of neurological score (3.8±0.6). The expression levels of TNF-α and COX-2 in the cerebral cortex detected by immunohistochemical staining were significantly decreased in CUD003 treated rats compared to the control rats. These results suggest that CUD003 mitigated the cerebral injury and neurological impairment during acute phase of cerebral ischemia-reperfusiom, which may be mediated by its anti-inflammatory effect.