title: Ischemic stroke injury is mediated by aberrant Cdk5.
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.
authors.affiliation: Department of Psychiatry.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Meyer
authors.affiliation: Department of Psychiatry.
authors.forename: Melissa I
authors.initials: MI
authors.lastname: Torres-Altoro
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9183.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: 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.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9183.
authors.forename: Vincent
authors.initials: V
authors.lastname: DiNapoli
authors.affiliation: Department of Psychiatry.
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.affiliation: Department of Psychiatry.
authors.forename: Janice W
authors.initials: JW
authors.lastname: Kansy
authors.affiliation: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505.
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Benkovic
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9530.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
authors.affiliation: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9183.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Rosen
authors.affiliation: Department of Psychiatry, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, james.bibb@utsouthwestern.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D002154:Calpain / Q000494:pharmacology; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000378:metabolism* / Q000628:therapy; D008297:Male; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology* / Q000517:prevention & control*; D009474:Neurons / Q000502:physiology; D010770:Phosphotransferases; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
chemical_list: C492236:Cdk5r1 protein, mouse; D004967:Estrogens; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D010959:Tissue Plasminogen Activator; D002154:Calpain
keywords: Cdk5; biomarker; calpain; ischemia; neuroprotection; stroke