Ischemic stroke injury is mediated by aberrant Cdk5.
J Neurosci
; 34(24): 8259-67, 2014 Jun 11.
Article
in En
| MEDLINE
| ID: mdl-24920629
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Infarction, Middle Cerebral Artery
/
Cyclin-Dependent Kinase 5
/
Nervous System Diseases
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Neurosci
Year:
2014
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA