Abstract
Glycogen synthase kinase-3 (GSK-3) is involved in the pathogenesis of several neurodegenerative diseases. In addition, as oxidative stress has been implicated in all neurodegenerative disorders, the inhibition of both pathways offers a potential strategy for preventing or delaying neurodegeneration. We examined the cytoprotective effects of lithium and SB-415286, two inhibitors of GSK-3, using a rat B65 cell line and also in cerebellar granule cells (CGN). H(2)O(2) decreased the inactive form of GSK-3 (phospho-GSK-3 at Ser9), as measured by immunoblot experiments involving an antibody against the inactive form of the enzyme. Moreover, lithium inhibited this effect. While SB-415286 exerted a protective effect, lithium did not attenuate the toxic effects of H(2)O(2) (1mM). We then examined those mechanisms implicated in the protective effects of SB-415286. When we analyzed reactive oxygen species (ROS) production using the fluorescent probe 2,7-dichlorodihydrofluorescein diacetate in B65 cells, as well as in CGN, we found that SB-415286 strongly reduced DCF fluorescence. Lithium, however, did not exhibit any antioxidant properties. We conclude that the GSK-3 inhibitor SB-415286 has antioxidant properties, which may explain the cytoprotective effects against H(2)O(2) damage. Furthermore, inhibition of GSK-3 activity was not involved in this protective effect.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminophenols / pharmacology*
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Animals
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Animals, Newborn
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Cell Line, Tumor
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Cells, Cultured
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Cytoprotection / drug effects
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Cytoprotection / physiology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Inhibitors / pharmacology
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Fluorescent Dyes / chemistry
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Hydrogen Peroxide / antagonists & inhibitors
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Hydrogen Peroxide / toxicity
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Indicators and Reagents / chemistry
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Lithium / pharmacology
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Maleimides / pharmacology*
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Neuroblastoma
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Neurodegenerative Diseases / drug therapy*
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Neurodegenerative Diseases / enzymology
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Neurodegenerative Diseases / prevention & control
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Neurons / drug effects*
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Neurons / enzymology
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Neuroprotective Agents / pharmacology*
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Oxidants / antagonists & inhibitors
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Oxidants / toxicity
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Oxidative Stress / drug effects*
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Oxidative Stress / physiology
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
Substances
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3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
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Aminophenols
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Enzyme Inhibitors
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Fluorescent Dyes
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Indicators and Reagents
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Maleimides
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Neuroprotective Agents
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Oxidants
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Reactive Oxygen Species
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Lithium
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Hydrogen Peroxide
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3