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Top priorities for cerebroprotective studies : a paradigm shift

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Lyden, P. D., Buchan, A. M., Boltze, Johannes and Fisher, M. (2021) Top priorities for cerebroprotective studies : a paradigm shift. Stroke, 52 (9). pp. 3063-3071. doi:10.1161/STROKEAHA.121.034947

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Official URL: https://doi.org/10.1161/STROKEAHA.121.034947

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Abstract

Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR (Stroke Treatment Academic Industry Roundtable) conferences identified both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in workshop no. 1 Top Priorities for Neuroprotection sought to redefine the neuroprotection paradigm and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term brain cytoprotection or cerebroprotection to replace the term neuroprotection when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although “time is still brain,” tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a tissue window to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term target window to suggest therapies that target the different elements of the neurovascular unit at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised, and enhanced the STAIR preclinical recommendations for developing new treatments in 2 phases: an exploratory qualification phase and a definitive validation phase. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood-brain barrier. Before clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multicenter, collaborative testing, for example, network trials. In the absence of a proven cerebroprotective agent to use as a gold standard, however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Cerebral ischemia, Cerebral ischemia -- Diagnosis, Cerebral ischemia -- Treatment , Cerebrovascular disease -- Diagnosis, Blood-brain barrier , Reperfusion (Physiology) , Neuroprotective agents
Journal or Publication Title: Stroke
Publisher: Lippincott Williams & Wilkins
ISSN: 0039-2499
Official Date: September 2021
Dates:
DateEvent
September 2021Published
22 July 2021Available
6 May 2021Accepted
Volume: 52
Number: 9
Page Range: pp. 3063-3071
DOI: 10.1161/STROKEAHA.121.034947
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
U24 NS113452National Institute of Neurological Disorders and Strokehttp://dx.doi.org/10.13039/100000065
R01NS075930National Institute of Neurological Disorders and Strokehttp://dx.doi.org/10.13039/100000065
Contributors:
ContributionNameContributor ID
Research GroupSTAIR XI Consortium, UNSPECIFIED

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