Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS

Exp Neurol. 2007 Jun;205(2):336-46. doi: 10.1016/j.expneurol.2007.03.004. Epub 2007 Mar 12.

Abstract

Glycogen synthase kinase (GSK)-3 has recently been implicated in the pathogenesis of neurodegenerative diseases. Although the neuroprotective effects of GSK-3 inhibitors in Alzheimer's disease have been established, their effects on amyotrophic lateral sclerosis (ALS) have not been well defined. This study was undertaken to evaluate the effects of GSK-3 inhibition in the G93A-SOD1 mouse model of ALS. Groups of G93A-SOD1 mice were treated with varying concentrations of GSK-3 inhibitor VIII, a specific GSK-3 inhibitor that crosses the BBB, intraperitoneally 5 days a week after 60 days of age. The GSK-3 inhibitor VIII treatment significantly delayed the onset of symptoms and prolonged the life span of the animals, and inhibited the activity of GSK-3 in a concentration-dependent manner. Furthermore, this treatment preserved survival signals and attenuated death and inflammatory signals. These data suggest that GSK-3 plays an important role in the pathogenic mechanisms of ALS and that inhibition of GSK-3 could be a potential therapeutic candidate for ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Blotting, Western
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Cyclooxygenase 2 / metabolism
  • Cytochromes c / metabolism
  • Cytosol / enzymology
  • Disease Progression
  • Enzyme Inhibitors / therapeutic use*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / genetics*
  • Humans
  • In Situ Nick-End Labeling
  • Intercellular Adhesion Molecule-1 / metabolism
  • Mice
  • Mice, Transgenic
  • Motor Neurons / pathology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Postural Balance / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1
  • Thiazoles / therapeutic use
  • Urea / analogs & derivatives
  • Urea / therapeutic use

Substances

  • Enzyme Inhibitors
  • SOD1 protein, human
  • Thiazoles
  • Intercellular Adhesion Molecule-1
  • N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
  • Urea
  • Cytochromes c
  • Cyclooxygenase 2
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Poly(ADP-ribose) Polymerases
  • Glycogen Synthase Kinase 3
  • Caspase 3