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Cerebral ischemia is a major cause of brain dysfunction. The E3 ubiquitin ligase anaphase-promoting complex and its coactivator Cdh1 have been reported to be involved in the regulation of neuronal survival, differentiation, axonal growth and synaptic development in the central nervous system. However, its role in the ischemic brain and the underlying mechanisms remain poorly understood. The present study aimed to investigate the effects of Cdh1 overexpression on the ischemic rat brain by direct intra-hippocampal injection of lentivirus-delivered Cdh1 before transient global cerebral ischemia reperfusion. Spatial memory acquisition and retention were assessed using a Morris water maze task. Neuronal damage, glial activation, oxidative stress and the synaptic ultrastructure were also examined. The results indicated that a recombinant Cdh1-encoding lentiviral vector can upregulate the expression of Cdh1 in the rat hippocampus. Cdh1 overexpression increased the survival rates of rats, reversed the abnormal accumulation of cyclin B1, alleviated neuronal death, inhibited glial activation, mitigated oxidative stress, modulated synaptic plasticity and improved neurological deficits caused by ischemia. Our study indicates that targeting the Cdh1 signaling pathway in the hippocampus may provide a promising therapeutic strategy for the clinical treatment of transient global cerebral ischemia.Using rat overexpression, we characterized a role for Cdh1 in the ischemic brain.Cdh1 enhanced survival rates and ameliorated cognitive deficits after ischemia reperfusion.Cdh1 alleviated neuronal death, inhibited glial activation, and mitigated oxidative stress.Neuroprotection by Cdh1 was observed at the molecular and ultrastructural level.