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

J Am Heart Assoc. 2019 May 7;8(9):e011851. doi: 10.1161/JAHA.118.011851.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology
  • Brain Ischemia / prevention & control*
  • Carbon Monoxide / metabolism
  • Carbon Monoxide / pharmacology*
  • Disease Models, Animal
  • Heart Arrest / drug therapy*
  • Heart Arrest / metabolism
  • Heart Arrest / pathology
  • Heart Arrest / physiopathology
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Organometallic Compounds / metabolism
  • Organometallic Compounds / pharmacology*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Time Factors
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • Neuroprotective Agents
  • Organometallic Compounds
  • Reactive Oxygen Species
  • tricarbonylchloro(glycinato)ruthenium(II)
  • Carbon Monoxide
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase