Research Article: Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models

Date Published: July 5, 2017

Publisher: Public Library of Science

Author(s): Alex Dyson, Felipe Dal-Pizzol, Giovanni Sabbatini, Anna B. Lach, Federica Galfo, Juliano dos Santos Cardoso, Bruna Pescador Mendonça, Iain Hargreaves, Bernardo Bollen Pinto, Daniel I. Bromage, John F. Martin, Kevin P. Moore, Martin Feelisch, Mervyn Singer, Karim Brohi

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.

Partial Text: 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. Following injurious reduction 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].

The last decade has seen considerable interest in sulfide as a putative adjunctive therapy during resuscitation from various acute and critical illness states. Initial studies involved administration of H2S gas and simple, inorganic sulfide salts (Na2S and NaHS) that, when dissolved, undergo instantaneous “generation” (rather than release) of sulfide [25]. Use of the latter has implications for both safety and efficacy, and most likely precluded the clinical development of treatments with these salts. More sophisticated drug design was clearly needed, and, as such, a diverse range of slow-release sulfide “donors” have been synthesized. These range from phosphinodithioate analogues (e.g., GYY4137), dithiolethiones, and sulfide-hybrid drugs (e.g., S-diclofenac) to persulfide-, gem-dithiol-, and N-mercapto-based donors [26–33].



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