Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS.
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.
Koh
Seong-Ho
SH
Department of Neurology, College of Medicine, Hanyang University, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-791, South Korea.
Kim
Youngchul
Y
Kim
Hyun Y
HY
Hwang
Sejin
S
Lee
Chang Ho
CH
Kim
Seung H
SH
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D004856:Postural Balance / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013844:Thiazoles / Q000627:therapeutic use; D014508:Urea / Q000031:analogs & derivatives / Q000627:therapeutic use
D004791:Enzyme Inhibitors; C000606290:SOD1 protein, human; D013844:Thiazoles; D018799:Intercellular Adhesion Molecule-1; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D045304:Cytochromes c; D051546:Cyclooxygenase 2; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D011065:Poly(ADP-ribose) Polymerases; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3