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Neuroscience. 2015 Apr 2;290:552-60. doi: 10.1016/j.neuroscience.2015.01.054. Epub 2015 Feb 7.

The inhibition of Cdk5 activity after hypoxia/ischemia injury reduces infarct size and promotes functional recovery in neonatal rats.

Author information

1
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou City, Jiangsu Province, China; The Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province, China.
2
Department of Neurology, Suzhou Kowloon Hospital, 118 Wansheng Street, Suzhou City, China.
3
The Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province, China.
4
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou City, Jiangsu Province, China.
5
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: Yfeng@emory.edu.
6
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou City, Jiangsu Province, China; The Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province, China. Electronic address: Xingshunxu@suda.edu.cn.

Abstract

Recent studies indicate that over-activation of Cdk5 is a crucial pro-death signal and Cdk5 activity inhibition provides neuroprotection in animal stroke models. However, Cdk5 inhibitors are reported to affect physiological functions of Cdk5 and lead to serious side effects. Therefore, targeting Cdk5 or its activators without affecting physiological functions of Cdk5 is a therapeutic strategy for ischemic brain injury. In this study, we examined Cdk5 activity in a rat hypoxia/ischemia (HI) injury model. Cdk5 expression was not changed after HI injury, but Cdk5 activity significantly increased, which was demonstrated by the increased phorsphorylation-phosphorylation of Tau and glucocorticoid receptor (GR), two downstream signals of Cdk5. We further showed that the levels of Cdk5 activators p35 and p39 decreased after HI injury, while p25, which is converted from p35 and has a higher activator activity on Cdk5, increased markedly after HI injury. P5, a 24-residue mimetic peptide of p35, was reported to specifically inhibit the p25/Cdk5 signal pathway in an Alzheimer's disease model. P5-TAT, which can cross the blood-brain barrier and cell membrane facilitated by TAT protein, was used in our study. We found that p5-TAT treatment did not change the levels of p35, p39, and p25, but reduced the phorsphorylation of Tau and GR, suggesting the inhibition of the p25/Cdk5 by the peptide p5-TAT. This was supported by the fact that p5 interacted with Cdk5, but not with Cdk5 activators. In addition, p5-TAT reduced cleaved caspase-3 level, a marker of neuronal apoptosis. We further demonstrated that p5-TAT pre-treatment reduced cerebral infarct volume; even when p5-TAT was delayed to be administered at 24h after HI injury, p5-TAT still promoted long-term functional recovery. Therefore, Cdk5 inhibition by the small peptide p5-TAT or its derivatives is a promising therapeutic strategy for the treatment of ischemic brain injury including hypoxic-ischemic encephalopathy and stroke.

KEYWORDS:

Cdk5; apoptosis; hypoxia/ischemia injury; p35; p35 mimetic peptide

[Indexed for MEDLINE]

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