Background Dysfunctional mitochondria are associated with neurological injury after cardiac arrest ( CA ). Although carbon monoxide ( CO ) has shown various potential therapeutic effects in preclinical tissue injury models, its mechanism of action in CA remains unclear. We sought to investigate the effects of a novel CO -releasing molecule on cerebral mitochondrial dysfunction and neurological injury after CA . Methods and Results Male Sprague-Dawley rats aged 20 to 22 months were subjected to 6-minute asphyxia CA before receiving CO treatment. Survival, neurologic deficit scores, neuronal death, mitochondrial function, and autophagy were evaluated after the return of spontaneous circulation. Results showed that CO post-treatment increased 3-day survival rate from 25% to 70.83% and reduced neurologic deficit scores. CO also ameliorated CA -induced neuronal apoptosis and necrosis in the cerebral cortex and improved cerebral mitochondrial function by reducing reactive oxygen species, reversing mitochondrial membrane potential depolarization, and preventing cytochrome C release. Furthermore, CO increased mitochondrial autophagy by inducing mitochondrial accumulation of PINK 1 ( PTEN -induced putative kinase 1) and Parkin. Downregulation of PINK 1 with genetic silencing si RNA abolished CO -afforded mitochondrial autophagy. Conclusions Taken together, our results indicate, for the first time, that CO treatment confers neuroprotection against ischemic neurological injury after CA possibly by promoting mitochondrial autophagy.
Keywords: cardiac arrest; mitochondria; mitochondrial autophagy; neuroprotection.