线粒体靶向硫化氢供体AP39可改善小鼠心脏骤停后的神经学预后。
Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice.
作者信息
Ikeda Kohei, Marutani Eizo, Hirai Shuichi, Wood Mark E, Whiteman Matthew, Ichinose Fumito
机构信息
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Bioscience, College of Life and Environmental Science, University of Exeter, UK.
出版信息
Nitric Oxide. 2015 Sep 15;49:90-6. doi: 10.1016/j.niox.2015.05.001. Epub 2015 May 7.
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.
目的
线粒体靶向硫化氢供体AP39，即[(10-氧代-10-(4-(3-硫代-3H-1,2-二硫醇-5-基)苯氧基)癸基)三苯基溴化鏻]，在体外对氧化应激具有细胞保护作用。我们研究了AP39是否能改善心脏骤停（CA）和心肺复苏（CPR）小鼠的神经功能及长期生存率。
方法
成年C57BL/6雄性小鼠经历8分钟的心脏骤停及随后的心肺复苏。我们研究了在心肺复苏前2分钟静脉注射AP39（10、100、1000 nmol·kg⁻¹）或赋形剂的效果（实验1）。评估全身氧化应激水平、线粒体通透性转换和组织学脑损伤。我们还研究了自主循环恢复（ROSC）后1分钟静脉注射AP39（10、1000 nmol·kg⁻¹）或赋形剂的效果（实验2）。ROSC定义为窦性心律恢复，平均动脉压>40 mmHg且持续至少10秒。
结果
接受CA/CPR治疗的赋形剂处理小鼠神经功能较差，10天生存率较低（实验1为15%，实验2为23%）。在心肺复苏前2分钟给予AP39（100和1000 nmol·kg⁻¹）可显著改善CA/CPR后的神经功能和10天生存率（分别为54%和62%）。心肺复苏前给予AP39可减轻CA/CPR后的线粒体通透性转换孔开放、活性氧生成和神经元变性。ROSC后1分钟给予10 nmol·kg⁻¹的AP39可显著改善CA/CPR后的神经功能和10天生存率（69%），但1000 nmol·kg⁻¹剂量时无此效果。
结论
目前的结果表明，在心肺复苏时或ROSC后给予线粒体靶向硫化物供体AP39，通过维持线粒体完整性和降低氧化应激，可改善CA/CPR后的神经功能和长期生存率。
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