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
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy*
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Amyotrophic Lateral Sclerosis / genetics*
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Blotting, Western
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Caspase 3 / metabolism
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Cell Death / drug effects
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Cyclooxygenase 2 / metabolism
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Cytochromes c / metabolism
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Cytosol / enzymology
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Disease Progression
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Enzyme Inhibitors / therapeutic use*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / genetics*
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Humans
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In Situ Nick-End Labeling
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Intercellular Adhesion Molecule-1 / metabolism
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Mice
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Mice, Transgenic
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Motor Neurons / pathology
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Poly(ADP-ribose) Polymerases / metabolism
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Postural Balance / drug effects
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Spinal Cord / metabolism
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Spinal Cord / pathology
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Superoxide Dismutase / genetics*
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Superoxide Dismutase-1
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Thiazoles / therapeutic use
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Urea / analogs & derivatives
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Urea / therapeutic use
Substances
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Enzyme Inhibitors
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SOD1 protein, human
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Thiazoles
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Intercellular Adhesion Molecule-1
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N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
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Urea
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Cytochromes c
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Cyclooxygenase 2
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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Poly(ADP-ribose) Polymerases
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Glycogen Synthase Kinase 3
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Caspase 3