Ischemic stroke injury is mediated by aberrant Cdk5

Details

• Personal Author:
  Benkovic SA ; Bibb JA ; Calabresi P ; Di Filippo M ; DiNapoli V ; Greengard P ; Huber JD ; Kansy JW ; Meyer DA ; Miller DB ; Plattner F ; Rosen CL ; Tan Z ; Torres-Altoro MI ; Tozzi A
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Biomarkers Cardiovascular Diseases Cardiovascular System Laboratories Occupational Health Safety
• Keywords:
  Author Keywords: Biomarker Calpain Cardiac-function Cardiovascular-disease Cardiovascular-function Cardiovascular-system-disease Cdk5 Cell-damage Cellular-function Heart Ischemia Laboratory-animals Laboratory-testing Medical-treatment Nerve-damage Nerve-function Neuroprotection Neurotransmitters Pharmacodynamics Proteins Stroke

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• ISSN:
  0270-6474
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2 ; OSHA Region 3 ; OSHA Region 6 ; Texas ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  34
• Issue:
  24
• NIOSHTIC Number:
  nn:20044563
• Citation:
  J Neurosci 2014 Jun; 34(24):8259-8267
• Contact Point Address:
  James A. Bibb, PhD, Departments of Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX 75390
• CAS Registry Number:
  Calpain (CAS RN 78990-62-2)
• Federal Fiscal Year:
  2014
• NORA Priority Area:
  Healthcare and Social Assistance ; Transportation, Warehousing and Utilities
• Peer Reviewed:
  True
• Source Full Name:
  The Journal of Neuroscience
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:232b0b0168f1c528a4d8336fa3e77e25f8b6306ef84dc689b15d0d320aac89549d6c73b329148817c8b050d6ef80590d0b0a147a8bf56c21bfe3d62ef02a535e
• Download URL:
  https://stacks.cdc.gov/view/cdc/200239/cdc_200239_DS1.pdf
• File Type:
  [PDF - 2.79 MB ]