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Objective: We determined the effects of ischemic preconditioning (IP) on apoptosis in a rat model of brain injury induced by cerebral ischemia/reperfusion following a moderate hypothermic low-flow (MHLF) procedure. Methods: A total of 180 rats were randomly divided into three groups. The surgery group was subjected to body temperature reduction and bilateral common carotid artery occlusion for 120 min at 25 ± 0.5°C, followed by artery reopening and rewarming. The sham-surgery group underwent the same procedure, but common carotid arteries were not occluded. The ischemic preconditioning-treated surgery group was pretreated with four cycles of 2 min occlusion of bilateral common carotid arteries and 5 min reperfusion, before 120 min of cerebral ischemia. Regional cerebral blood flow was measured continuously in 10 rats per group using laser Doppler flowmetry. We investigated brain cell apoptosis levels and mitochondrial apoptosis signaling pathway components at various time points following reperfusion. Results: The ischemic preconditioning-treated surgery group displayed decreases in apoptotic cell numbers and apoptotic protein expression levels after the procedure at 6 h, 24 h, 72 h, and 7 d. Ischemic preconditioning inhibited cytochrome c release, caspase-3 activation, and mitochondrial apoptosis signaling pathway activation. Conclusion: The protective effects of ischemic preconditioning were associated with a reduction of DNA fragmentation, and inhibition of mitochondrial cytochrome c release and caspase-3 activation, which alleviated cerebral ischemia/reperfusion injury after moderate hypothermic low flow in rats. These findings highlight the potential of ischemic preconditioning as a neuroprotective therapy for surgery involving MHLF. [ABSTRACT FROM AUTHOR]