Wang Li-Li, Li Jimei, Gu Xiaohuan, Wei Ling, Yu Shan Ping
Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology, Emory University, School of Medicine, Atlanta, GA, USA.
Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Int J Dev Neurosci. 2017 Apr;57:77-84. doi: 10.1016/j.ijdevneu.2017.01.002. Epub 2017 Jan 19.
Glycogen synthase kinase 3β (GSK3β) was originally identified as a regulator for glycogen metabolism and is now an important therapeutic target for a variety of brain disorders including neurodegenerative diseases due to it's pivotal role in cellular metabolism, proliferation and differentiation. In the development of stroke therapies focusing on tissue repair and functional recovery, promoting neurogenesis is a main approach in regenerative medicine. In the present investigation, we explored the effects of a GSK3β specific inhibitor, 6-Bromoindirubin-3'-oxime (BIO), on regenerative activities of neuroblasts in the subventricular zone (SVZ) and functional recovery after focal cerebral ischemia. Adult C57/BL mice were subjected to occlusion of distal branches of middle cerebral artery (MCA) supplying the sensorimotor barrel cortex. Three days later, BIO (8.5μg/kg, i.p.) was administered every 2days until sacrificed at 14 or 21days after stroke. The BIO treatment significantly increased generation of neuroblasts labeled with BrdU and BrdU/doublecortin (DCX) in the SVZ. Comparing to vehicle controls, increased number of neuroblasts migrated to the peri-infarct region where they differentiate into mature neurons. Along with the elevated BDNF expression at the peri-infarct area, the number of newly formed neurons was significantly increased. BIO treatment significantly enhanced sensorimotor functional recovery after the focal ischemia. It is suggested that the GSK3 signaling may be a potential therapeutic target for regenerative treatment after ischemic stroke.
糖原合酶激酶3β（GSK3β）最初被鉴定为糖原代谢的调节因子，由于其在细胞代谢、增殖和分化中的关键作用，现在已成为包括神经退行性疾病在内的多种脑部疾病的重要治疗靶点。在专注于组织修复和功能恢复的中风治疗开发中，促进神经发生是再生医学的主要方法。在本研究中，我们探讨了GSK3β特异性抑制剂6-溴靛玉红-3'-肟（BIO）对脑室下区（SVZ）神经母细胞再生活性和局灶性脑缺血后功能恢复的影响。成年C57/BL小鼠接受供应感觉运动桶状皮质的大脑中动脉（MCA）远端分支闭塞。三天后，每2天腹腔注射BIO（8.5μg/kg），直至在中风后14或21天处死。BIO治疗显著增加了SVZ中用BrdU和BrdU/双皮质素（DCX）标记的神经母细胞的生成。与载体对照相比，迁移到梗死周围区域并分化为成熟神经元的神经母细胞数量增加。随着梗死周围区域BDNF表达的升高，新形成的神经元数量显著增加。BIO治疗显著增强了局灶性缺血后的感觉运动功能恢复。提示GSK3信号通路可能是缺血性中风后再生治疗的潜在靶点。
