Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Sci Rep. 2017 Jan 3;7:40013. doi: 10.1038/srep40013.
Cyclin-dependent kinase 5 (CDK5) is a multifaceted protein shown to play important roles in the central nervous system. Abundant evidence indicates that CDK5 hyperactivities associated with neuronal apoptosis and death following ischemic stroke. CDK5 activity increases when its cofactor p35 cleaves into p25 during ischemia. Theoretically, inhibition of CDK5/p25 activity or reduction of p25 would be neuroprotective. TFP5, a modified 24-aa peptide (Lys254-Ala277) derived from p35, was found to effectively inhibit CDK5 hyperactivity and improve the outcomes of Alzheimer's disease and Parkinson's disease in vivo. Here, we showed that intraperitoneal injection of TFP5 significantly decreased the size of ischemia in early-stage of adult ischemic stroke rats. Relative to controls, rats treated with TFP5 displayed reduced excitotoxicity, neuroinflammation, apoptosis, astrocytes damage, and blood-brain barrier disruption. Our findings suggested that TFP5 might serve as a potential therapeutic candidate for acute adult ischemic stroke.
周期蛋白依赖性激酶 5（CDK5）是一种多功能蛋白，在中枢神经系统中发挥着重要作用。大量证据表明，CDK5 的过度活跃与缺血性中风后神经元凋亡和死亡有关。当 CDK5 的辅助因子 p35 在缺血期间切割成 p25 时，CDK5 的活性会增加。从理论上讲，抑制 CDK5/p25 活性或减少 p25 会具有神经保护作用。TFP5 是一种经过修饰的 24 个氨基酸肽（Lys254-Ala277），来源于 p35，被发现可有效抑制 CDK5 的过度活跃，并改善体内阿尔茨海默病和帕金森病的预后。在这里，我们表明，TFP5 的腹腔注射可显著减小成年缺血性中风大鼠早期的缺血面积。与对照组相比，用 TFP5 治疗的大鼠表现出兴奋性毒性、神经炎症、细胞凋亡、星形胶质细胞损伤和血脑屏障破坏减少。我们的研究结果表明，TFP5 可能成为急性成年缺血性中风的潜在治疗候选药物。
