title: GSK-3β Inhibition Induced Neuroprotection, Regeneration, and Functional Recovery After Intracerebral Hemorrhagic Stroke.
abstract: Hemorrhagic stroke is a devastating disease that lacks effective therapies. In the present investigation, we tested 6-bromoindirubin-3'-oxime (BIO) as a selective glycogen synthase kinase-3β (GSK-3β) inhibitor in a mouse model of intracerebral hemorrhage (ICH). ICH was induced by injection of collagenase IV into the striatum of 8- to 10-week-old C57BL/6 mice. BIO (8 μg/kg, IP) was administered following either an acute delivery (0-2 h delay) or a prolonged regimen (every 48 h starting at 3 days post-ICH). At 2 days post-ICH, the acute BIO treatment significantly reduced the hematoma volume. In the perihematoma regions, BIO administration blocked GSK-3β phosphorylation/activation, increased Bcl-2 and β-catenin levels, and significantly increased viability of neurons and other cell types. The prolonged BIO regimen maintained a higher level of β-catenin, upregulated VEGF and BDNF, and promoted neurogenesis and angiogenesis in peri-injury zones at 14 days after ICH. The BIO treatment also promoted proliferation of neural stem cells (NSCs) and migration of nascent DCX+ neuroblasts from the subventricular zone (SVZ) to the lesioned cortex. BIO improved functional outcomes on both the neurological severity score and rotarod tests. The findings of this study corroborate the neuroprotective and regenerative effects of BIO and suggest that the Wnt/GSK-3β/β-catenin pathway may be explored for the treatment of acute or chronic ICH.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zheng Zachory
authors.initials: ZZ
authors.lastname: Wei
authors.forename: James Ya
authors.initials: JY
authors.lastname: Zhang
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Soonmi
authors.initials: S
authors.lastname: Won
authors.forename: Jinmei
authors.initials: J
authors.lastname: Sun
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.forename: Jimei
authors.initials: J
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000089662:Doublecortin Protein; D005260:Female; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000627:therapeutic use; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D010091:Oximes / Q000627:therapeutic use; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: C483321:6-bromoindirubin-3'-oxime; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D007211:Indoles; D010091:Oximes; D007770:L-Lactate Dehydrogenase; D038362:Glycogen Synthase Kinase 3; D005947:Glucose; D010100:Oxygen