Inhibition of glycogen synthase kinase 3 increased subventricular zone stem cells proliferation

Biomed Pharmacother. 2017 Sep;93:1074-1082. doi: 10.1016/j.biopha.2017.07.043. Epub 2017 Jul 18.

Abstract

The effects of Wnt signaling modifiers on cell proliferation, seem to be cell specific. Enhancing the proliferation of subventricular zone (SVZ) progenitors has been in the focus of research in recent years. Here we investigate the effect of CHIR99021, a Glycogen Synthase Kinase 3 (GSk-3) inhibitor, on SVZ progenitor's proliferation both in vivo and in vitro. Neural stem cells were extracted from the adult C57bl/6 by mincing and trypsin treatment followed by culturing in specific medium. Sphere cells formed within about 7-10days and were characterized by immunostaining. Number of spheres and their size was assessed following exposure to different concentration of CHIR99021 or vehicle. For in vivo studies, animals received intracerebroventricular (i.c.v.) injection of CHIR99021 or vehicle for four days. A subgroup of animals, after 4days treatment with CHIR99021 received intranasal kainic acid to induce local neurodegeneration in CA3 area of hippocampus. Inhibition of GSk-3 by CHIR99021 increased neural progenitor proliferation and the effect of CHIR99021 was long lasting so that the treated cells showed higher proliferation even after CHIR99021 removal. In vivo administration of CHIR99021 increased the number of neural progenitors at the rims of lateral ventricles especially when the treatment was followed by kainic acid administration which induces neural insult. Results showed that direct administration of CHIR99021 into the culture medium or animal brain increased the number of SVZ progenitors, especially when a neural insult was induced in the hippocampus.

Keywords: CHIR99021; Glycogen synthase kinase 3; Kainic acid; Neural progenitors; Wnt signaling.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Lateral Ventricles / drug effects*
  • Lateral Ventricles / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects

Substances

  • Chir 99021
  • Pyridines
  • Pyrimidines
  • Glycogen Synthase Kinase 3