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Author Notes:

Address correspondence to Ling Wei, M.D., Departments of Anesthesiology and Neurology, Emory University School of Medicine, 101 Woodruff Circle WMRB 617, Atlanta, GA 30322, USA. Tel: 404-712-8661; Fax: 404-727-6300; E-mail: lwei7@emory.edu or Jimei Li, M.D., Department of Neurology, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Xi-Cheng District, Beijing 100050, P.R. China. Tel: 010-63014411; E-mail: lijimei2002@yahoo.com.cn

We are grateful to Dr. Jin Hwan Lee for his valuable advice on animal behavior tests.

The authors declare no conflicts of interest.

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Research Funding:

This work was supported by the NIH (grants NS062097 to L.W., NS085568 to L.W./S.P.Y., and NS091585 to L.W.), VA National Merit (grant RX000666 to S.P.Y.), AHA Predoctoral Fellowships (grant 16PRE31230001 to J.Y.Z.) and Postdoctoral Fellowship (grant 15POST25710112 to Z.Z.W.), National Natural Science Foundation of China (grants 81371355/81500989/81671191 to Y.Z. and 81571104 to J.L.), and Beijing Natural Science Foundation (grant 7142045 to Y.Z.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell & Tissue Engineering
  • Medicine, Research & Experimental
  • Transplantation
  • Cell Biology
  • Research & Experimental Medicine
  • 6-Bromoindirubin-3 '-oxime (BIO)
  • Wnt signaling
  • Neural stem cells (NSCs)
  • Neurogenesis
  • Intracerebral hemorrhage (ICH)
  • PHARMACOLOGICALLY INDUCED HYPOTHERMIA
  • NEURAL PROGENITOR CELLS
  • FOCAL CEREBRAL-ISCHEMIA
  • MESENCHYMAL STEM-CELLS
  • INTRAVENTRICULAR HEMORRHAGE
  • NEURONAL DIFFERENTIATION
  • MAMMALIAN TARGET
  • SURVIVAL FACTORS
  • NERVOUS-SYSTEM
  • BRAIN-INJURY

GSK-3 beta Inhibition Induced Neuroprotection, Regeneration, and Functional Recovery After Intracerebral Hemorrhagic Stroke

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Journal Title:

Cell Transplantation

Volume:

Volume 26, Number 3

Publisher:

, Pages 395-407

Type of Work:

Article | Final Publisher PDF

Abstract:

Hemorrhagic strok e 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-3b (GSK-3b) 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-3b phosphorylation/activation, increased Bcl-2 and b-catenin levels, and significantly increased viability of neurons and other cell types. The prolonged BIO regimen maintained a higher level of b-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-3b/b-catenin pathway may be explored for the treatment of acute or chronic ICH.

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© 2017 Cognizant, LLC.

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