Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Abstract

Background: Several 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 results: Brain 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 (antioxidant 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 proinflammatory cytokine levels and nitric oxide products.Conclusion: ATTM 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.

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…However, in clinical trials patients were not given these drugs until 6 h later ( Green and Shuaib, 2006 ). Despite these setbacks, researchers are continuously developing new methods and refining models, as well as investigating novel avenues of research that hold significant promise in improving stroke outcome ( Silasi et al, 2015 ; Gouveia et al, 2017 ; Kannangara et al, 2018 ; Freitas-Andrade et al, 2019 ; Hill et al, 2020 ; Mendonca et al, 2020 ; Rayasam et al, 2020 ; Zhang et al, 2020 ). A greater appreciation for the role of physical rehabilitation and insight into the molecular mechanisms at play has led to a significant impact on the quality of life after stroke ( Fang et al, 2019 ; McDonald et al, 2019 ; Sun and Zehr, 2019 ).…”

Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4–7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia–Reperfusion

“…The tMCAO model was induced by endovascular occlusion of the right middle cerebral artery using a monofilament (Doccol Corporation, Sharon, MA, USA) for 90 min and was performed under the control of magnetic resonance imaging (MRI), as described previously [22]. Ninety-minute tMCAO in rodents is an adequate duration of occlusion and has been used in numerous studies of the molecular mechanisms of ischemia-reperfusion (IR) damage and the effects of neuroprotective agents on the infarct area [47][48][49][50].…”

Biological Connection of Psychological Stress and Polytrauma under Intensive Care: The Role of Oxytocin and Hydrogen Sulfide

“…Undesired side effects were due to the narrow timing and dosing window [159] and the potentially high H 2 S peak concentrations [160] when the H 2 S-releasing salts NaSH and/or Na 2 S were used, or the aggravation of shock due to the vasodilatory properties of so-called slow-releasing H 2 S donors [161]. The latter problems may be overcome by evaluating already approved drugs, especially for potential clinical use, such as ammonium tetrathiomolybdate (approved for the treatment of Wilson's disease) [155,162] or STS, a drug devoid of major undesired side effects and approved as an antidote for cyanide and mustard gas poisoning, cis-platinum overdose in oncology, and calciphyllaxy in endstage kidney disease [163]. Ammonium tetrathiomolybdate prevented organ failure and morphological damage after cerebral and myocardial ischemia and hemorrhagic shock in mice [155,162]; however, none of the experimental groups received standard clinical therapy.…”

“…The latter problems may be overcome by evaluating already approved drugs, especially for potential clinical use, such as ammonium tetrathiomolybdate (approved for the treatment of Wilson's disease) [155,162] or STS, a drug devoid of major undesired side effects and approved as an antidote for cyanide and mustard gas poisoning, cis-platinum overdose in oncology, and calciphyllaxy in endstage kidney disease [163]. Ammonium tetrathiomolybdate prevented organ failure and morphological damage after cerebral and myocardial ischemia and hemorrhagic shock in mice [155,162]; however, none of the experimental groups received standard clinical therapy. Experimental data are also available for STS in organ protection after burns [164], myocardial infarction [165], and E. coli septicemia [166].…”