This Article Full Text Full Text (PDF) All Versions of this Article: 40/9/3149    most recent STROKEAHA.108.543769v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Vosler, P. S. Articles by Chen, J. PubMed PubMed Citation Articles by Vosler, P. S. Articles by Chen, J. Pubmed/NCBI databases Medline Plus Health Information Stroke Related Collections Apoptosis Neuroprotectors Other Stroke Treatment - Medical

(Stroke. 2009;40:3149.)
© 2009 American Heart Association, Inc.

Topical Review

Mitochondrial Targets for Stroke

Focusing Basic Science Research Toward Development of Clinically Translatable Therapeutics

Peter S. Vosler, BSc; Steven H. Graham, MD, PhD; Lawrence R. Wechsler, MD Jun Chen, MD

From the Department of Neurology (P.S.V., S.H.G., L.R.W., J.C.), University of Pittsburgh School of Medicine, Pa; State Key Laboratory of Medical Neurobiology (J.C.), Fudan University School of Medicine, Shanghai, China; and the Geriatric Research, Educational, and Clinical Center (S.H.G., J.C.), Veterans Affairs Pittsburgh Health Care System, Pa.

Correspondence to Dr Jun Chen, Department of Neurology, S-507, Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. E-mail chenj2{at}upmc.edu

Eng Lo MD Section Editor

Background and Purpose— Stroke is a major cause of death and disability, and it is imperative to develop therapeutics to mitigate stroke-related injury. Despite many promising prospects, attempts at translating neuroprotective agents that show success in animal models of stroke have resulted in very limited clinical success.

Summary of Review— This review discusses reasons for the lack of translational success based on the therapeutic targets tested and the pathophysiology of stroke. New recanalization therapies and alternative therapeutic strategies are discussed concerning mitochondria-mediated cell death. Mitochondrial death-regulation pathways are divided into 3 categories: Upstream signaling pathways, agents that target mitochondria directly, and downstream death-execution effectors. The apoptosis signal-related kinase/c-Jun-terminal kinase pathway is used as an example to provide rationale as to why inhibiting signaling pathway upstream of mitochondrial dysfunction is a promising therapeutic approach. Finally, the mechanisms of autophagy and mitochondrial biogenesis are discussed in relation to stroke.

Conclusions— Increasing evidence suggests that reperfusion is necessary for improved neurological outcomes after stroke. Development of improved recanalization methods with increased therapeutic windows will aid in improving clinical outcome. Adjunct neuroprotective interventions must also be developed to ensure maximal brain tissue salvage. Targeting prodeath signaling pathways upstream of mitochondrial damage is promising for potential clinically effective treatment. Further understanding of the roles of equilibrium of autophagy and mitochondrial biogenesis in the pathogenesis of stroke could also lead to novel therapeutics.

Key Words: cerebral ischemia • therapeutics • neuroprotection • mitochondria