Blood–brain barrier (BBB) disruption, inflammation, and cell death are the pathogenic mechanisms of cerebralischemia/reperfusion (I/R) injury. Nicorandil protects ischemic injury via some of these mechanisms. The aimof this study was to investigate the therapeutic effects of this drug on the brain ischemia after transient middlecerebral artery occlusion (MCAO) and clarify the NF-kappa B and Nrf2-dependent mechanisms modulated by thisdrug. Sixty-six rats were randomized into sham, MCAO and MCAO + nicorandil groups with oral gavage for3 days. Cerebral I/R injury were induced by a transient MCAO for 1 h and neurobehavioral scores wereperformed for 3 days. In addition to measurement of BBB disruption and brain water content, the total andinfarct volume, density, and total number of neurons, non-neurons and dead neurons in the right cortex wereestimated by unbiased stereological methods. RT-PCR was performed to analyze the expression levels of NF-kappa Band Nrf2. Although nicorandil treatment in the sub-acute brain ischemia did not have a prominent effect onneurobehavioral function and number of neurons, non-neurons and dead neurons probably through up-regulationof NF-kappa B, it, however, improved ischemia-induced BBB disruption and brain edema and showed asignificant reduction in the infarction volume probably through up-regulation of Nrf2.