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

Bruna Pescador Mendonça,Ana Carolina Vieira,Monique Michels,Alex Dyson,Juliano Dos Santos Cardoso,Felipe Dal-Pizzol,Andressa Manfredini,Mervyn Singer,Diogo Wendhausen

doi:10.1186/s40635-020-00300-8

Bruna Pescador Mendonça, Ana Carolina Vieira + Show 7 more

Open Access

https://doi.org/10.1186/s40635-020-00300-8

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Abstract

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.

Highlights

Stroke is the third leading cause of death in developed countries [1], the principal cause of severe long-term disability worldwide [2], and the largest contributor to global neurological disability-adjusted life-years [3]
The batch of ammonium tetrathiomolybdate (ATTM) we used in this study conformed to our predefined criteria for sulfide release (Fig. 2)
No deaths were deemed to be drug-related as a similar number of animals from each group succumbed to early demise (9 saline-treated vs 8 ATTM-treated; Fig 1)

Summary

Introduction

Stroke is the third leading cause of death in developed countries [1], the principal cause of severe long-term disability worldwide [2], and the largest contributor to global neurological disability-adjusted life-years [3]. Advances such as thrombolytic therapy and angioplasty have revolutionized acute management [4, 5]; this obligatory revascularization induces further injury through reperfusion. Drug design of sulfide mimetics gained sophistication, with characterization of several classes of sulfur-hybrid molecules and slow-release sulfide “donors”. These enable more controlled sulfide release (to more accurately reflect those derived from endogenous sources) and better targeting to the intended (intracellular) site of action [21]. We hypothesized that ATTM could confer neuroprotection in a relevant rodent model of regional stroke

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