Ischemic stroke injury is mediated by aberrant Cdk5

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 th...

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Bibliographic Details
Published in:The Journal of neuroscience 2014-06, Vol.34 (24), p.8259-8267
Main Authors: Meyer, Douglas A, Torres-Altoro, Melissa I, Tan, Zhenjun, Tozzi, Alessandro, Di Filippo, Massimiliano, DiNapoli, Vincent, Plattner, Florian, Kansy, Janice W, Benkovic, Stanley A, Huber, Jason D, Miller, Diane B, Greengard, Paul, Calabresi, Paolo, Rosen, Charles L, Bibb, James A
Format: Article
Language:English
Subjects:
Animals
Calpain - pharmacology
Cell Death - genetics
Cell Death - physiology
Corpus Striatum - drug effects
Corpus Striatum - pathology
Cyclin-Dependent Kinase 5 - genetics
Cyclin-Dependent Kinase 5 - metabolism
Disease Models, Animal
Estrogens - metabolism
Female
Glial Fibrillary Acidic Protein - metabolism
Hypoxia - physiopathology
In Vitro Techniques
Infarction, Middle Cerebral Artery - complications
Infarction, Middle Cerebral Artery - metabolism
Infarction, Middle Cerebral Artery - therapy
Male
Mice, Knockout
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Nervous System Diseases - etiology
Nervous System Diseases - prevention & control
Neurons - physiology
Phosphotransferases
Rats
Rats, Sprague-Dawley
Tetrazolium Salts
Time Factors
Tissue Plasminogen Activator - therapeutic use
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Summary: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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/JNEUROSCI.4368-13.2014