RT Journal Article
SR Electronic
T1 Ischemic Stroke Injury Is Mediated by Aberrant Cdk5
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8259
OP 8267
DO 10.1523/JNEUROSCI.4368-13.2014
VO 34
IS 24
A1 Meyer, Douglas A.
A1 Torres-Altoro, Melissa I.
A1 Tan, Zhenjun
A1 Tozzi, Alessandro
A1 Di Filippo, Massimiliano
A1 DiNapoli, Vincent
A1 Plattner, Florian
A1 Kansy, Janice W.
A1 Benkovic, Stanley A.
A1 Huber, Jason D.
A1 Miller, Diane B.
A1 Greengard, Paul
A1 Calabresi, Paolo
A1 Rosen, Charles L.
A1 Bibb, James A.
YR 2014
UL http://www.jneurosci.org/content/34/24/8259.abstract
AB 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.