Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models.
Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models.
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DOI：
10.1371/journal.pmed.1002310
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发表时间：
2017-07
期刊：
影响因子：
15.8
通讯作者：
Singer M
中科院分区：
文献类型：
--
作者：
Dyson A;Dal-Pizzol F;Sabbatini G;Lach AB;Galfo F;Dos Santos Cardoso J;Pescador Mendonça B;Hargreaves I;Bollen Pinto B;Bromage DI;Martin JF;Moore KP;Feelisch M;Singer M
缺血器官的早期血运重建是改善预后的关键，但随之而来的再灌注损伤可能是有害的。再灌注损伤主要是由于线粒体产生过量的活性氧（ROS）。硫化物抑制线粒体并减少ROS的产生。四硫代钼酸铵（ATTM）是一种铜螯合剂，以可控和新颖的方式释放硫化物，并可能提供潜在的治疗用途。在体外，ATTM释放硫化物的时间，pH值，温度和硫醇依赖性的方式。与标准硫化物发生器相比，ATTM的受控硫化物释放降低了清醒大鼠体内和骨骼肌组织离体的代谢（测量为耗氧量），具有上级安全性。在大鼠再灌注/复苏时静脉注射ATTM，可显着减少心肌或脑缺血后的梗死面积，并在严重出血后提供生存益处。机制研究（体外缺氧/复氧）证明了线粒体作用位点（MitoSOX荧光降低），其中产生了大多数破坏性ROS。无机硫代金属酸盐ATTM代表了一类新的硫化物释放药物。我们的研究结果为进一步研究这种化合物作为再灌注损伤的新辅助治疗提供了动力。在临床前大鼠损伤模型中，Alex Dyson及其同事研究了四硫代钼酸铵在缺血后恢复血流后保护器官免受损伤的潜力。再灌注损伤是由缺血器官的血流恢复引起的，例如，在心肌或脑血管重建术或从出血中复苏之后。再灌注损伤可能与初始缺血事件一样严重，但目前尚无批准的治疗方法。已知硫化物释放药物在动物模型中对再灌注损伤有效，但迄今为止还没有在患者中显示出疗效，并且安全性问题已经提出。我们发现，四硫代钼酸铵（ATTM）以受控的方式释放硫化物，并可能符合所需的疗效和安全性。ATTM释放硫化物的化学性质不同于其他释放硫化物的药物类别。在我们的动物模型中，ATTM降低了氧代谢，防止心脏病发作、中风和出血后的再灌注损伤和器官损伤，结果显著改善，安全性良好。我们发现了一类新型的硫化物释放药物。在我们的动物模型中，ATTM保护身体器官免受缺血组织再灌注引起的损伤。ATTM可以作为一种短期的保护性治疗方法用于患者，同时为大脑和心脏等主要器官供血的血管被打开，或者在严重出血的复苏过程中。有效性和安全性（短期和长期）需要在人类中进行探索。如果ATTM能够成功开发，它可以显着减少心脏病发作，中风，出血和其他缺血/再灌注条件后的长期器官损伤。
Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility. In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced. The inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury. In preclinical rat injury models Alex Dyson and colleagues investigate the potential of ammonium tetrathiomolybdate to protect organs from injury after restoration of blood flow following ischemia. Reperfusion injury results from restoration of blood flow to ischemic organs, e.g., following myocardial or cerebral revascularization or resuscitation from hemorrhage. Reperfusion injury may be as severe as the initial ischemic event, yet there is no currently approved treatment. Sulfide-releasing drugs are known to be effective against reperfusion injury in animal models, but none to date have shown efficacy in patients, and safety concerns have been raised. We found that ammonium tetrathiomolybdate (ATTM) releases sulfide in a controlled manner and potentially fits the desired efficacy and safety profile. The chemical nature of sulfide release from ATTM differs from that of other sulfide-releasing drug classes. In our animal models, ATTM decreased oxygen metabolism and protected against reperfusion injury and organ damage following heart attack, stroke, and hemorrhage, with significant improvements in outcome, and a good safety profile. We have discovered a novel class of sulfide-releasing drugs. In our animal models, ATTM protected body organs from damage induced by reperfusion of ischemic tissues. ATTM could be potentially used in patients as a short-term protective therapy while blocked blood vessels feeding major organs such as the brain and heart are being opened up, or during resuscitation from severe bleeding. Effectiveness and safety (short- and long-term) need to be explored in humans. If ATTM can be successfully developed, it could significantly reduce long-term organ damage after heart attack, stroke, hemorrhage, and other ischemia/reperfusion conditions.