Reconsidering Neuroprotection in the Reperfusion Era

Savitz, Sean I; Baron, Jean‐Claude; Yenari, Midori A.; Sanossian, Nerses; Fisher, Marc

doi:10.1161/strokeaha.117.017283

Cited by 166 publications

(195 citation statements)

References 44 publications

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“…During ischemia, the tissue area at risk will contain both salvageable and nonsalvageable cells. While the new stroke reperfusion era has revolutionized management by improving short-and long-term outcomes, the necessary revascularization-induced reperfusion injury has become a major therapeutic target [43]. During initial reperfusion, salvageable cells are subjected to a nutrient supply in excess of their metabolic requirements, and this disproportionate substrate provision drives mitochondrial respiration to a level that generates large quantities of damaging ROS [26].…”

Section: Discussionmentioning

confidence: 99%

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

Mendonça¹,

Cardoso²,

Michels³

et al. 2020

ICMx

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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.

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Section: Discussionmentioning

confidence: 99%

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

Mendonça¹,

Cardoso²,

Michels³

et al. 2020

ICMx

View full text Add to dashboard Cite

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“…Several subjects completed only two to three cycles of perconditioning because of the time from their admission to the catheter laboratory was too short to perform the four cycles that the investigation required. Therefore, much earlier (e.g., in prehospital scenarios) initiation of RIC may be a better choice for future studies; it would not only give enough time for four cycles of RIC but also preserve more brain tissue at risk of infarction . In addition, the perconditioning protocol has yet to be defined: two or three cycles of stimuli might have similar protective effects as four cycles.…”

Section: Discussionmentioning

confidence: 99%

Remote ischemic conditioning for acute stroke patients treated with thrombectomy

Zhao

Che

et al. 2018

Ann Clin Transl Neurol

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ObjectiveRemote ischemic conditioning (RIC) has been demonstrated to be safe and feasible for patients with acute ischemic stroke (AIS), as well as for those receiving intravenous thrombolysis. We assessed the safety and feasibility of RIC for AIS patients undergoing endovascular treatment (ET).MethodsWe conducted a pilot study with patients with AIS who were suspected of having an emergent large‐vessel occlusion in the anterior circulation and who were scheduled for ET within 6 hours of ictus. Four cycles of RIC were performed before recanalization, immediately following recanalization, and once daily for the subsequent 7 days. The primary outcome was any serious RIC‐related adverse events.ResultsTwenty subjects, aged 66.1 ± 12.1 years, were recruited. No subject experienced serious RIC‐related adverse events. The intracranial pressure, cranial perfusion pressure, mean arterial pressure, heart rate, middle cerebral artery peak systolic flow velocity, and pulsatility index did not change significantly before, during, or after the limb ischemia (P > 0.1 for all). Of 80 cycles, 71 (89%) were completed before recanalization and 80 (100%) were completed immediately after recanalization; 444 of 560 cycles (78%) were completed within 7 days posttreatment. No patients had to stop RIC because it affected routine clinical managements. Six subjects (30%) experienced intracerebral hemorrhage, which was symptomatic in one case (5%). At the 3‐month follow‐up, 11 subjects (55%) had achieved functional independence, and two subjects (10%) died.Interpretation RIC appears to be safe and feasible for patients with AIS undergoing ET. Investigations are urgently needed to determine the efficacy of RIC in this patient population.

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“…In addition, efforts are needed to harmonize biomarker assessment and improve secured portability of data for analysis between research collaborators [12]. Last, the importance of finding cytoprotective agents in the postendovascular therapy era will require effective biomarkers [8,20]. Neuroprotective agents thus far have failed to effectively translate to clinical application, but appropriately selected biomarkers may revive this effort [13].…”

Section: Challenges In Biomarker Utilizationmentioning

confidence: 99%

Biomarker Application for Precision Medicine in Stroke

Simpkins

Janowski

et al. 2019

Transl. Stroke Res.

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Stroke remains one of the leading causes of long-term disability and mortality despite recent advances in acute thrombolytic therapies. In fact, the global lifetime risk of stroke in adults over the age of 25 is approximately 25%, with 24.9 million cases of ischemic stroke and 18.7 million cases of hemorrhagic stroke reported in 2015. One of the main challenges in developing effective new acute therapeutics and enhanced long-term interventions for stroke recovery is the heterogeneity of stroke, including etiology, comorbidities, and lifestyle factors that uniquely affect each individual stroke survivor. In this comprehensive review, we propose that future biomarker studies can be designed to support precision medicine therapeutic interventions after stroke. The current challenges in defining ideal biomarkers for stroke are highlighted, including consideration of disease course, age, lifestyle factors, and subtypes of stroke. This overview of current clinical trials includes biomarker collection, and concludes with an example of biomarker design for aneurysmal subarachnoid hemorrhage. With the advent of "-omics" studies, neuroimaging, big data, and precision medicine, well-designed stroke biomarker trials will greatly advance the treatment of a disease that affects millions globally every year.

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Reconsidering Neuroprotection in the Reperfusion Era

Cited by 166 publications

References 44 publications

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

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

Remote ischemic conditioning for acute stroke patients treated with thrombectomy

Biomarker Application for Precision Medicine in Stroke

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