Meyer Douglas A, Torres-Altoro Melissa I, Tan Zhenjun, Tozzi Alessandro, Di Filippo Massimiliano, DiNapoli Vincent, Plattner Florian, Kansy Janice W, Benkovic Stanley A, Huber Jason D, Miller Diane B, Greengard Paul, Calabresi Paolo, Rosen Charles L, Bibb James A
Department of Psychiatry.
Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9183.
J Neurosci. 2014 Jun 11;34(24):8259-67. doi: 10.1523/JNEUROSCI.4368-13.2014.
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.
缺血性中风是发病和死亡的主要原因之一。治疗选择有限，只有少数患者接受急性干预。了解介导神经元损伤和死亡的机制可能会确定神经保护治疗的靶点。在此，我们表明蛋白激酶Cdk5的异常活性是啮齿动物中风期间神经元死亡的主要原因。体内栓塞性大脑中动脉闭塞（MCAO）或脑片氧糖剥夺诱导的缺血导致Cdk5激活辅因子p35钙蛋白酶依赖性转化为p25。缺血期间抑制异常的Cdk5可保护多巴胺神经传递、维持场电位并阻断兴奋性毒性。此外，Cdk5的药理学抑制或条件性敲除（CKO）可防止神经元因缺血而死亡。此外，Cdk5 CKO显著减少了MCAO后的梗死面积。因此，针对异常的Cdk5活性可能是治疗中风的有效方法。
