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Ischemic stroke injury is mediated by aberrant Cdk5.
Meyer DA; Torres-Altoro MI; Tan Z; Tozzi A; Di Filippo M; DiNapoli V; Plattner F; Kansy JW; Benkovic SA; Huber JD; Miller DB; Greengard P; Calabresi P; Rosen CL; Bibb JA
J Neurosci 2014 Jun; 34(24):8259-8267
Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.
Cardiac-function; Cardiovascular-function; Cardiovascular-system-disease; Cardiovascular-disease; Heart; Biomarkers; Proteins; Nerve-function; Cellular-function; Nerve-damage; Cell-damage; Laboratory-animals; Laboratory-testing; Neurotransmitters; Pharmacodynamics; Medical-treatment; Author Keywords: biomarker; calpain; Cdk5; ischemia; neuroprotection; stroke
James A. Bibb, PhD, Departments of Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX 75390
Issue of Publication
Healthcare and Social Assistance; Transportation, Warehousing and Utilities
The Journal of Neuroscience
TX; WV; NY
Page last reviewed: July 1, 2022
Content source: National Institute for Occupational Safety and Health Education and Information Division