Free radical induced neural damage is implicated in cerebral ischemia-reperfusion (IR) injury and antioxidants are reported to have neuroprotective activity. The present study was designed to assess the neuroprotective role of rutin (Vitamin P), and mechanism of action. The middle cerebral artery (MCA) of an adult male Wistar rat was occluded for 2 h and reperfused for 22 h. The administration of rutin (25 mg/kg bwt., orally) once daily for 21 days before middle cerebral artery occlusion (MCAO) showed marked reduction in infarct size, reduced the neurological deficits in terms of behaviors, suppressed neuronal loss and diminished the p53 expression in MCAO rats. A significantly depleted activity of antioxidant enzymes, glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD) and content of glutathione (GSH) in MCAO group were protected significantly in MCAO group pretreated with rutin. Conversely, the elevated level of thiobarbituric acid reactive species (TBARS), H(2)O(2) and protein carbonyl (PC) in MCAO group was attenuated significantly in rutin-pretreated group when compared with MCAO group. These results indicate that rutin attenuates ischemic neural apoptosis by reducing the expression of p53, preventing morphological changes and increasing endogenous antioxidant enzymatic activities. Thus, rutin treatment may represent a novel approach in lowering the risk or improving the function of ischemia-reperfusion brain injury-related disorders.