Research Report Glycogen synthase kinase-3β activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells Kyu-Yong Lee a,1 , Seong-Ho Koh a,1 , Min Young Noh a , Kun-Woo Park b , Young Joo Lee a , Seung Hyun Kim a, ⁎ a Department of Neurology, Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, Korea b Department of Neurology, Korea University, School of Medicine, Seoul, Korea ARTICLE INFO ABSTRACT Article history: Accepted 26 October 2006 Available online 8 December 2006 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 μMH 2 O 2 , 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 H 2 O 2 -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. © 2006 Elsevier B.V. All rights reserved. Keywords: Neuronal cell death Apoptosis Neurodegenerative disease Glycogen synthase kinase-3β Oxidative stress 1. Introduction Glycogen synthase kinase-3 (GSK-3), originally identified as a regulator of glycogen metabolism (Embi et al., 1980), is now implicated as a multifaceted enzyme affecting a diverse range of biological functions including gene expression, cellular archi- tecture, and apoptosis (Jope and Johnson, 2004). Two closely related isoforms, GSK-3α and GSK-3β, have been shown to be present in mammals (Woodgett, 1991). In particular, GSK-3β is well known to play critical roles in oxidative stress-induced neuronal cell death mechanisms (Bijur and Jope, 2000, 2001; Grimes and Jope, 2001; Koh et al., 2003, 2004a,b; Takadera and Ohyashiki, 2004; Watcharasit et al., 2003). Activated GSK-3β, which inhibits heat shock transcription factor (HSTF)-1 and BRAIN RESEARCH 1129 (2007) 89 – 99 ⁎ Corresponding author. Fax: +82 2 2296 8370. E-mail address: kimsh1@hanyang.ac.kr (S.H. Kim). 1 Contributed equally as first authors. 0006-8993/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2006.10.055 available at www.sciencedirect.com www.elsevier.com/locate/brainres