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 tetrathiomolyb...
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| Format: | Article |
| Language: | English |
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SpringerOpen
2020-04-01
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| Series: | Intensive Care Medicine Experimental |
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| Online Access: | http://link.springer.com/article/10.1186/s40635-020-00300-8 |
| _version_ | 1818151419495055360 |
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| author | Bruna Pescador Mendonça Juliano Dos Santos Cardoso Monique Michels Ana Carolina Vieira Diogo Wendhausen Andressa Manfredini Mervyn Singer Felipe Dal-Pizzol Alex Dyson |
| author_facet | Bruna Pescador Mendonça Juliano Dos Santos Cardoso Monique Michels Ana Carolina Vieira Diogo Wendhausen Andressa Manfredini Mervyn Singer Felipe Dal-Pizzol Alex Dyson |
| author_sort | Bruna Pescador Mendonça |
| collection | DOAJ |
| description | 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 (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. |
| first_indexed | 2024-12-11T13:38:32Z |
| format | Article |
| id | doaj.art-218fe208575247bc940c98e54311c8a1 |
| institution | Directory Open Access Journal |
| issn | 2197-425X |
| language | English |
| last_indexed | 2024-12-11T13:38:32Z |
| publishDate | 2020-04-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Intensive Care Medicine Experimental |
| spelling | doaj.art-218fe208575247bc940c98e54311c8a12022-12-22T01:04:55ZengSpringerOpenIntensive Care Medicine Experimental2197-425X2020-04-018111410.1186/s40635-020-00300-8Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional strokeBruna Pescador Mendonça0Juliano Dos Santos Cardoso1Monique Michels2Ana Carolina Vieira3Diogo Wendhausen4Andressa Manfredini5Mervyn Singer6Felipe Dal-Pizzol7Alex Dyson8Laboratory of Experimental Pathophysiology, University of Southern Santa CatarinaLaboratory of Experimental Pathophysiology, University of Southern Santa CatarinaLaboratory of Experimental Pathophysiology, University of Southern Santa CatarinaLaboratory of Experimental Pathophysiology, University of Southern Santa CatarinaLaboratory of Experimental Pathophysiology, University of Southern Santa CatarinaLaboratory of Experimental Pathophysiology, University of Southern Santa CatarinaBloomsbury Institute for Intensive Care Medicine, Division of Medicine, University College LondonLaboratory of Experimental Pathophysiology, University of Southern Santa CatarinaLaboratory of Experimental Pathophysiology, University of Southern Santa CatarinaAbstract 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.http://link.springer.com/article/10.1186/s40635-020-00300-8IschemiaReperfusionBrainOxidative stressReactive oxygen speciesMitochondria |
| spellingShingle | Bruna Pescador Mendonça Juliano Dos Santos Cardoso Monique Michels Ana Carolina Vieira Diogo Wendhausen Andressa Manfredini Mervyn Singer Felipe Dal-Pizzol Alex Dyson Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke Intensive Care Medicine Experimental Ischemia Reperfusion Brain Oxidative stress Reactive oxygen species Mitochondria |
| 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 | Ischemia Reperfusion Brain Oxidative stress Reactive oxygen species Mitochondria |
| url | http://link.springer.com/article/10.1186/s40635-020-00300-8 |
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