Delayed Treatment of 6-Bromoindirubin-3′-oxime Stimulates Neurogenesis and Functional Recovery after Focal Ischemic Stroke in Mice

• Type of Material: Article
• Authors: Li-Li Wang, Capital Medical University; Jimei Li, Capital Medical University; Xiaohuan Gu, Emory University; Ling Wei, Emory University; Shan Ping Yu, Emory University
• Language: English
• Date: 2017-04-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 ISDN
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ijdevneu.2017.01.002
• Title of Journal or Parent Work: International Journal of Developmental Neuroscience
• ISSN: 0736-5748
• Volume: 57
• Start Page: 77
• End Page: 84
• Grant/Funding Information: This work is supported by NIH grants NS085568 (LW/SPY), NS073378 (SPY), VA National Merit Award RX000666 (SPY) and a grant (81350012) from National Natural Science Foundation of China (JL).; This work was also supported by the NIH grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.
• Keywords: INHIBITION; Regeneration; Neurosciences & Neurology; Cerebral ischemia; ADULT BRAIN; ENHANCES ANGIOGENESIS; STEM-CELLS; MIDDLE CEREBRAL-ARTERY; Science & Technology; Neurosciences; NEURAL PROGENITOR CELLS; DIFFERENTIATION; MIGRATION; Life Sciences & Biomedicine; Developmental Biology; GSK3 beta inhibitor; 6-Bromoindirubin-3 '-oxime (BIO); Wnt; Functional recovery; EXPRESSION; BARREL CORTEX
• Research Categories: Biology, Neuroscience; Health Sciences, Medicine and Surgery

Abstract

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 (8.5 μg/kg, i.p.) was administered every 2 days until sacrificed at 14 or 21 days 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.