Objective@#To evaluate the effect of irisin preconditioning on global cerebral ischemia-reperfusion (I/R) injury in rats.@*Methods@#Thirty-six healthy male Sprague-Dawley rats, aged 8-10 weeks, weighing 250-300 g, were divided into 3 groups (n=12 each) using a random number table method: sham operation group (group S), global cerebral I/R group (group I/R) and irisin preconditioning group (group I). Global cerebral I/R was induced by occlusion of bilateral common carotid arteries combined with hypotension (MAP maintained at 35-45 mmHg) in anesthetized rats.At 30 min before ischemia, irisin 10 μg/kg (diluted to 10 μg/ml in normal saline) was intravenously injected in group I, and the equal volume of normal saline was intravenously injected in S and I/R groups.Morris water maze test was performed at day 3 of reperfusion to assess the cognitive function.Rats were sacrificed after the end of morris water maze test, and brains were removed for determination of histopathologic changes in hippocampal CA1 region (using HE staining), neuronal apoptosis in hippocampal CA1 region (Tunel staining), glial fibrillary acidic protein (GFAP) expression (by Western blot), myeloperoxidase (MPO) activity in the hippocampal tissues (by colorimetric assay), and contents of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) in hippocampal tissues (by enzyme-linked immunosorbent assay). The cell necrosis rate and apoptotic rate were calculated.@*Results@#Compared with group S, the escape latency was significantly prolonged on 1-5 days in group I/R and on 1-3 days in group I, the time of staying at 1st quadrant was significantly shortened, the cell necrosis rate and apoptotic rate were increased, the expression of GFAP was up-regulated, and the activity of MPO and contents of TNF-α and IL-1β were increased in I/R and I groups (P<0.05 or 0.01). Compared with group I/R, the escape latency was significantly shortened on 1-5 days, the time of staying at 1st quadrant was prolonged, the cell necrosis rate and apoptotic rate were decreased, the expression of GFAP was down-regulated, and the MPO activity and contents of TNF-α and IL-1β were decreased in group I (P<0.05 or 0.01).@*Conclusion@#Irisin preconditioning can reduce the global cerebral I/R injury in rats, and the mechanism may be related to inhibiting activation of astrocytes in hippocampus and reducing inflammatory responses.