Abstract
BackgroundEarly 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.Methods and findingsIn 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.ConclusionsThe 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.
Highlights
Ischemia/reperfusion (I/R) injury is well recognized following multiple therapeutic interventions such as revascularization following myocardial ischemia or cerebrovascular thrombosis, resuscitation following hemorrhage, and organ transplantation
The inorganic thiometallate Ammonium tetrathiomolybdate (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
Summary
Ischemia/reperfusion (I/R) injury is well recognized following multiple therapeutic interventions such as revascularization following myocardial ischemia or cerebrovascular thrombosis, resuscitation following hemorrhage, and organ transplantation. Impact of tetrathiomolybdate on ischemia/reperfusion injury of blood flow to tissues, further damage is induced by reperfusion, necessarily caused by restoration of an adequate oxygen supply. Reperfusion injury is largely attributed to excess production of reactive oxygen species (ROS) by mitochondria [1]. Residual morbidity from both irreversible ischemia (from delayed intervention) and reperfusion injury (from the intervention itself) still represents a considerable social and economic healthcare burden, leading to chronic organ failure and a shortened lifespan. 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). Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility
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