ALDH 2 conferred neuroprotection on cerebral ischemic injury by alleviating mitochondria-related apoptosis through JNK/caspase-3 signing pathway.

Past studies have indicated that the dysregulation of Aldehyde dehydrogenase 2 (ALDH2) is related to the pathogenesis of acute stroke. However, the underlying mechanisms of ALDH2-mediated acute stroke are still not well understood. Thus, our study was designed to explore the influence of ALDH2 in acute stroke and determine whether its related mechanisms are involved in regulating mitochondria-associated apoptosis modulating JNK/caspase-3 pathway. In vitro analysis on the gain and loss of ALDH2 and JNK function were performed to explore its influence on OGD/R injury and relevant signaling pathways. Our findings suggested that ALDH2 expression was significantly down-regulated in rats suffering from acute stroke and also in primary cortical cultured neurons and PC12 cells upon OGD/R stimulation. ALDH2 overexpression markedly decreased infarct size and improved neurological outcomes. Furthermore, ALDH2 overexpression significantly suppressed stroke-induced mitochondria-associated apoptosis and inhibited p-JNK activation and p-JNK/caspase-3 complex formation. Similarly, in in vitro OGD/R models, ALDH2 reintroduction not only promoted cellular viability and moderated LDH release, but also inhibited mitochondria-related apoptosis. Moreover, JNK inhibition relieved OGD/R-induced cellular injury and apoptosis while JNK activation aggravated them. Furthermore, ALDH2 overexpression and JNK inhibition significantly reduced caspase-3 activation and transcription which was triggered by OGD/R damage. Caspase-3 activation and transcription also re-elevated during activation of JNK in ALDH2-reintroduced cells. Finally, ChIP assay revealed that p-JNK was bound to caspase-3 promoter. Collectively, ALDH2 overexpression led to a significant reduction in mitochondria-related apoptosis via JNK-mediated caspase-3 activation and transcription in both in vitro and in vivo cerebral ischemia models.