title: Delayed treatment of 6-Bromoindirubin-3'-oxime stimulates neurogenesis and functional recovery after focal ischemic stroke in mice.
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 (8.5μg/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.
authors.affiliation: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology, Emory University, School of Medicine, Atlanta, GA, USA.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Jimei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Emory University, School of Medicine, Atlanta, GA, USA.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, Emory University, School of Medicine, Atlanta, GA, USA; Department of Neurology, Emory University, School of Medicine, Atlanta, GA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, Emory University, School of Medicine, Atlanta, GA, USA. Electronic address: spyu@emory.edu.
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D020547:Lateral Ventricles / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D020127:Recovery of Function / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000209:etiology*; D013997:Time Factors
chemical_list: C483321:6-bromoindirubin-3'-oxime; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors; D007211:Indoles; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D010091:Oximes; D000071679:Glycogen Synthase Kinase 3 beta; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine
keywords: 6-Bromoindirubin-3′-oxime (BIO); Cerebral ischemia; Functional recovery; GSK3β inhibitor; Regeneration; Wnt