Glycogen synthase kinase-3beta activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells.
Glycogen synthase kinase-3, especially the beta form (GSK-3beta), plays key roles in oxidative stress-induced neuronal cell death, an important pathogenic mechanism of various neurodegenerative diseases. Although the neuroprotective effects of GSK-3beta inhibitors have been described, the optimal level of GSK-3beta inhibition for neuronal cell survival has not yet been determined. We investigated the effect of varying GSK-3beta activity on the viability of oxidative stress-injured neuronally differentiated PC12 (nPC12) cells and intracellular signals related with the GSK-3beta and caspase-3 pathways. Compared to the nPC12 control cells treated with only 100 microM H(2)O(2), treatment of 50-200 nM GSK-3beta inhibitor II or 25-500 nM GSK-3beta inhibitor VIII reduced the increased enzyme activity by about 50% and protected the cells against H(2)O(2)-induced oxidative stress. The optimal concentration of GSK-3beta inhibitor II enhanced heat shock transcription factor-1 levels, decreased levels of phosphorylated tau (Ser202) and cytosolic cytochrome c, activated caspase-3, and cleaved poly (ADP-ribose) polymerase. In contrast, higher concentrations of GSK-3beta inhibitor II (more than 500 nM) induced neuronal cell death and showed opposite effects relative to the above described intracellular signals. These results suggest that optimized inhibitor levels for modulating GSK-3beta activity may prevent apoptosis induced by oxidative stress associated with neurodegenerative diseases.
Lee
Kyu-Yong
KY
Department of Neurology, Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, Korea.
Koh
Seong-Ho
SH
Noh
Min Young
MY
Park
Kun-Woo
KW
Lee
Young Joo
YJ
Kim
Seung Hyun
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D000076249:Heat Shock Transcription Factors; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D018696:Neuroprotective Agents; D014157:Transcription Factors; D016875:tau Proteins; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3