Novel Role of Carbon Monoxide in Improving Neurological Outcome After Cardiac Arrest in Aged Rats: Involvement of Inducing Mitochondrial Autophagy.

Abstract

BackgroundDysfunctional 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 ResultsMale 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 PINK1 (PTEN‐induced putative kinase 1) and Parkin. Downregulation of PINK1 with genetic silencing siRNA abolished CO‐afforded mitochondrial autophagy.ConclusionsTaken together, our results indicate, for the first time, that CO treatment confers neuroprotection against ischemic neurological injury after CA possibly by promoting mitochondrial autophagy.