title: Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Eizo
authors.initials: E
authors.lastname: Marutani
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Department of Bioscience, College of Life and Environmental Science, University of Exeter, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.affiliation: University of Exeter Medical School, St. Luke's Campus, Exeter, England, UK. Electronic address: m.whiteman@exeter.ac.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: fichinose@mgh.harvard.edu.
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D006323:Heart Arrest / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020011:Protective Agents; D013876:Thiophenes; D006862:Hydrogen Sulfide
keywords: Cardiac arrest; Hydrogen sulfide; Mitochondria; Resuscitation