BackgroundCerebral stroke, known as a cerebral vascular accident (CVA), is one of the leading causes of long-term disability and the second leading cause of death worldwide. Despite amounts of advances that have been achieved in terms of the treatment of ischemic stroke. But thus far, clinically effective neuroprotectants remain elusive, which may mainly due to the lack of a complete understanding of molecular mechanisms of the stroke. Previous studies have been revealed that catestatin (Cst) is closely related to cardiovascular ischemia/reperfusion injuries. However, little is known about whether Cst is involved in the regulation of neuronal death processes during ischemia. MethodsIn the present study, we revealed a protective function of Cst on Rat neuron cell death in the setting of ischemia/reperfusion injury. ResultsWe found that Cst treatment significantly attenuated the deficits of hippocampal related behaviors. On mechanism, our data revealed that Cst administration remarkably reduced ER-stress and mitochondrial dysfunction caused by I/R injury, and subsequently protected brain cells from apoptosis. ConclusionIn sum, our results demonstrate that Cst ameliorates I/R injury-induced hippocampal-related behaviors deficits by protecting the neurons from I/R injury-induced ER-stress and mitochondrial dysfunction and apoptosis. Our findings may provide a promising novel neuroprotectant for ischemic stroke therapy.