disability and death in later life. The primary aim of therapeutic intervention for cerebral ischemia is to reduce the volume of brain damage and thus to minimize the neurological impairment. Because neuronal degeneration after cerebral ischemia can progress rapidly and is often irreversible, the benefit of effective pharmacological intervention is quite limited at present. The only medication proven to be effective and widely used at the acute stage of human stroke is tissue plasminogen activator (tPA). Tissue damage in cerebral ischemia is the result of a complex pathophysiological cascade. A rapid depletion of energy store triggers several cellular events, such as membrane depolarization and Ca influx, resulting in excitotoxic neuronal death. After reperfusion, oxygen influx with free radical production contributes to deterioration of surviving neuronal tissue. In addition to these intracellular events, a hypoxic condition caused by re-occlusion of microvasculature after reperfusion has been reported and believed to be one of the major causes of the development of neuronal damage. Tacrolimus (FK506), a macrolide immunosuppressant, has been used widely to prevent allograft rejection in organ transplantation. Immunosuppression is mediated by inhibition of calcineurin in T-cells, with subsequent failure of NF-AT to translocate into the nucleus and to induce transcription of IL2. In addition to its immunosuppressive effects, tacrolimus has been reported to exert neuroprotective activity in a variety of animal models of cerebral ischemia. The neuroprotective effect of tacrolimus has been explained by several mechanisms such as an anti-apoptotic effect via inhibition of cytochrome c release from mitochondria, an anti-inflammatory effect and so on. However, the neuroprotective mechanism of tacrolimus has not been fully elucidated. Tacrolimus has been reported to exert an anti-thrombotic effect and inhibit the expression of adhesion molecules in in vitro studies, however, no studies examining effect on the occurrence of re-occlusion of microvasculature in transient focal cerebral ischemia have been reported. With recent development of 2-nitroimidazole hypoxia markers (hypoxyprobe-1), it is now possible to detect the distribution of tissue hypoxia (pO2 10 mmHg) by using immunohistochemical technique. Using this method, we have previously reported that a hypoxic condition exists within cerebral cortex in rats at 3, 9 and 24 h after MCA occlusion for 60 min, and proposed that plugging of microvasculature with granulocytes and platelets would be responsible for the hypoxic condition. We also reported that tacrolimus attenuated cortical neuronal damage slightly at 9 h, with a significant effect at 24 h after MCA occlusion. In the present study, we therefore investigated the inhibitory effect of tacrolimus on accumulation of granulocytes and platelets and on tissue hypoxia at 9 and 24 h after transient focal cerebral ischemia in rats.