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J Neurosci. 2014 Jun 11;34(24):8259-67. doi: 10.1523/JNEUROSCI.4368-13.2014.

Ischemic stroke injury is mediated by aberrant Cdk5.

Author information

1
Department of Psychiatry.
2
Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9183.
3
Clinica Neurologica, Università di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy, Fondazione Santa Lucia-Istituto di Ricovero e Cura a Carattere Scientifico, 00184 Rome, Italy.
4
National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505.
5
Department of Basic Pharmaceutical Sciences, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9530.
6
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021.
7
Department of Psychiatry, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, james.bibb@utsouthwestern.edu.

Abstract

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.

KEYWORDS:

Cdk5; biomarker; calpain; ischemia; neuroprotection; stroke

PMID:
24920629
PMCID:
PMC4051977
DOI:
10.1523/JNEUROSCI.4368-13.2014
[Indexed for MEDLINE]
Free PMC Article

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