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

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 (AT...

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Autores principales: Mendonça, Bruna Pescador, Cardoso, Juliano Dos Santos, Michels, Monique, Vieira, Ana Carolina, Wendhausen, Diogo, Manfredini, Andressa, Singer, Mervyn, Dal-Pizzol, Felipe, Dyson, Alex
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145883/
https://www.ncbi.nlm.nih.gov/pubmed/32274608
http://dx.doi.org/10.1186/s40635-020-00300-8
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author Mendonça, Bruna Pescador
Cardoso, Juliano Dos Santos
Michels, Monique
Vieira, Ana Carolina
Wendhausen, Diogo
Manfredini, Andressa
Singer, Mervyn
Dal-Pizzol, Felipe
Dyson, Alex
author_facet Mendonça, Bruna Pescador
Cardoso, Juliano Dos Santos
Michels, Monique
Vieira, Ana Carolina
Wendhausen, Diogo
Manfredini, Andressa
Singer, Mervyn
Dal-Pizzol, Felipe
Dyson, Alex
author_sort Mendonça, Bruna Pescador
collection PubMed
description 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 (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. 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.
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spelling pubmed-71458832020-04-16 Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke Mendonça, Bruna Pescador Cardoso, Juliano Dos Santos Michels, Monique Vieira, Ana Carolina Wendhausen, Diogo Manfredini, Andressa Singer, Mervyn Dal-Pizzol, Felipe Dyson, Alex Intensive Care Med Exp Research 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 (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. 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. Springer International Publishing 2020-04-09 /pmc/articles/PMC7145883/ /pubmed/32274608 http://dx.doi.org/10.1186/s40635-020-00300-8 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Mendonça, Bruna Pescador
Cardoso, Juliano Dos Santos
Michels, Monique
Vieira, Ana Carolina
Wendhausen, Diogo
Manfredini, Andressa
Singer, Mervyn
Dal-Pizzol, Felipe
Dyson, Alex
Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
title Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
title_full Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
title_fullStr Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
title_full_unstemmed Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
title_short Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
title_sort neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145883/
https://www.ncbi.nlm.nih.gov/pubmed/32274608
http://dx.doi.org/10.1186/s40635-020-00300-8
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