NDRG4 protects against cerebral ischemia injury by inhibiting p53-mediated apoptosis.

Cerebral ischemia is one of the leading causes of death and long-term disability worldwide. N-myc downstream-regulated gene 4 (NDRG4) is predominantly expressed in the brain as well as in the heart and has been reported to be involved in resistance to neuronal cell death caused by ischemic injury. However, the underlying mechanism of NDRG4 in cerebral ischemia/reperfusion (I/R) injury remains unknown. Middle cerebral artery occlusion (MCAO) surgery was performed to establish a model of ischemic brain injury. We found that NDRG4 expression was upregulated during the early stage and decreased 24 h after ischemia/reperfusion (I/R) injury, and NDRG4 overexpression decreased the infarct size and mitigated the neurological deficits induced by I/R injury by inhibiting apoptosis. Furthermore, NDRG4 could interact with p53, inhibiting its expression and blocking p53-mediated mitochondrial apoptosis signaling. Moreover, p53 in turn inhibited NDRG4 expression in response to I/R injury, and inhibition of p53 alleviated cerebral I/R injury. Thus, our work provides a new mechanism for the role of NDRG4 in cerebral I/R injury and provides potential targets for future clinical therapies for stroke.