Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice

Abstract Aims Mitochondria-targeted hydrogen sulfide donor AP39, [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], exhibits cytoprotective effects against oxidative stress in vitro . We examined whether or not AP39 improves the neurological function and long term survival in mice subjected to cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Methods Adult C57BL/6 male mice were subjected to 8 min of CA and subsequent CPR. We examined the effects of AP39 (10, 100, 1000 nmol kg −1 ) or vehicle administered intravenously at 2 min before CPR (Experiment 1). Systemic oxidative stress levels, mitochondrial permeability transition, and histological brain injury were assessed. We also examined the effects of AP39 (10, 1000 nmol kg −1 ) or vehicle administered intravenously at 1 min after return of spontaneous circulation (ROSC) (Experiment 2). ROSC was defined as the return of sinus rhythm with a mean arterial pressure >40 mm Hg lasting at least 10 seconds. Results Vehicle treated mice subjected to CA/CPR had poor neurological function and 10-day survival rate (Experiment 1; 15%, Experiment 2; 23%). Administration of AP39 (100 and 1000 nmol kg −1 ) 2 min before CPR significantly improved the neurological function and 10-day survival rate (54% and 62%, respectively) after CA/CPR. Administration of AP39 before CPR attenuated mitochondrial permeability transition pore opening, reactive oxygen species generation, and neuronal degeneration after CA/CPR. Administration of AP39 1 min after ROSC at 10 nmol kg −1 , but not at 1000 nmol kg −1 , significantly improved the neurological function and 10-day survival rate (69%) after CA/CPR. Conclusion The current results suggest that administration of mitochondria-targeted sulfide donor AP39 at the time of CPR or after ROSC improves the neurological function and long term survival rates after CA/CPR by maintaining mitochondrial integrity and reducing oxidative stress.