Ammonium tetrathiomolybdate as a water-soluble and slow-release hydrogen sulfide donor.
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ABSTRACT:
SUBMITTER: Xu S
PROVIDER: S-EPMC4775341 | biostudies-literature | 2016 Mar
REPOSITORIES: biostudies-literature
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Ammonium tetrathiomolybdate as a water-soluble and slow-release hydrogen sulfide donor.
Xu Shi S Yang Chun-Tao CT Meng Fu-Hui FH Pacheco Armando A Chen Li L Xian Ming M
Bioorganic & medicinal chemistry letters 20160204 6
Ammonium tetrathiomolybdate (TTM) was found to be a slow hydrogen sulfide (H2S) releasing agent. Its H2S generation capability in aqueous solutions was confirmed by UV-vis and fluorescence assays. TTM also showed H2S-like cytoprotective effects in hydrogen peroxide (H2O2)-induced oxidative damage in HaCaT cells. ...[more]
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Project description:BackgroundSeveral therapeutic strategies to rescue the brain from ischemic injury have improved outcomes after stroke; however, there is no treatment as yet for reperfusion injury, the secondary damage caused by necessary revascularization. Recently we characterized ammonium tetrathiomolybdate (ATTM), a drug used as a copper chelator over many decades in humans, as a new class of sulfide donor that shows efficacy in preclinical injury models. We hypothesized that ATTM could confer neuroprotection in a relevant rodent model of regional stroke.Methods and resultsBrain ischemia was induced by transient (90-min) middle cerebral artery occlusion (tMCAO) in anesthetized Wistar rats. To mimic a clinical scenario, ATTM (or saline) was administered intravenously just prior to reperfusion. At 24 h or 7 days post-reperfusion, rats were assessed using functional (rotarod test, spontaneous locomotor activity), histological (infarct size), and molecular (anti-oxidant enzyme capacity, oxidative damage, and inflammation) outcome measurements. ATTM-treated animals showed improved functional activity at both 24 h and 7-days post-reperfusion, in parallel with a significant reduction in infarct size. These effects were additionally associated with increased brain antioxidant enzyme capacity, decreased oxidative damage, and a late (7-day) effect on pro-inflammatory cytokine levels and nitric oxide products.ConclusionATTM confers significant neuroprotection that, along with its known safety profile in humans, provides encouragement for its development as a novel adjunct therapy for revascularization following stroke.
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