Glycogen synthase kinase-3β activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells

Kyu Yong Lee, Seong Ho Koh, Min Young Noh, Kun Woo Park, Young Joo Lee, Seung Hyun Kim

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Glycogen synthase kinase-3, especially the beta form (GSK-3β), plays key roles in oxidative stress-induced neuronal cell death, an important pathogenic mechanism of various neurodegenerative diseases. Although the neuroprotective effects of GSK-3β inhibitors have been described, the optimal level of GSK-3β inhibition for neuronal cell survival has not yet been determined. We investigated the effect of varying GSK-3β activity on the viability of oxidative stress-injured neuronally differentiated PC12 (nPC12) cells and intracellular signals related with the GSK-3β and caspase-3 pathways. Compared to the nPC12 control cells treated with only 100 μM H2O2, treatment of 50-200 nM GSK-3β inhibitor II or 25-500 nM GSK-3β inhibitor VIII reduced the increased enzyme activity by about 50% and protected the cells against H2O2-induced oxidative stress. The optimal concentration of GSK-3β 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-3β 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-3β activity may prevent apoptosis induced by oxidative stress associated with neurodegenerative diseases.

Original languageEnglish
Pages (from-to)89-99
Number of pages11
JournalBrain Research
Volume1129
Issue number1
DOIs
Publication statusPublished - 2007 Jan 19

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Keywords

  • Apoptosis
  • Glycogen synthase kinase-3β
  • Neurodegenerative disease
  • Neuronal cell death
  • Oxidative stress

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

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