Epigallocatechin gallate prevents oxidative-stress-induced death of mutant Cu/Zn-superoxide dismutase (G93A) motoneuron cells by alteration of cell survival and death signals.
This study was undertaken to evaluate the effect of the G93A mutation in the human Cu/Zn-superoxide dismutase gene (hSOD1) on the phosphatidylinositol-3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3) pathway in motoneuron, and to determine the role of epigallocatechin gallate (EGCG) on oxidative stress-injured motoneurons. The viability of G93A mutant cells was less than that of wild-type cells, and the activation of PI3K and the phosphorylation of Akt and GSK-3 in G93A mutant cells decreased compared with wild-type hSOD1 4.1 cells. In the experiment to evaluate the effect of oxidative stress and/or EGCG on these motoneurons, after exposure to 400 microM H2O2, the MTT assay revealed greatly reduced viability of G93A mutant cells compared with wild-type cells, and pre-treatment of these cells with EGCG before H2O2 exposure increased the viability of both cell lines. Western blot analysis showed that the G93A mutation and oxidative stress decreased survival signals including PI3K/Akt but increased death signals including GSK-3; however, pre-treatment with EGCG increased survival signals but decreased death signals. These results suggest that PI3K/Akt and GSK-3 activities are altered in G93A mutant cells and EGCG-induced activation of PI3K/Akt and inhibition of GSK-3 could be a new potential therapeutic strategy for ALS associated with oxidative injury.
Koh
Seong-Ho
SH
Department of Neurology, College of Medicine, Hanyang University, #17 Haengdang-dong, Seongdong-ku, Seoul, Republic of Korea.
Kwon
Hyugsung
H
Kim
Kyung Suk
KS
Kim
Juhan
J
Kim
Myung-Ho
MH
Yu
Hyun-Jeung
HJ
Kim
Manho
M
Lee
Kwang-Woo
KW
Do
Byung Rok
BR
Jung
Hai Kwan
HK
Yang
Ki-Wha
KW
Appel
Stanley H
SH
Kim
Seung H
SH
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
D004338:Drug Combinations; D018696:Neuroprotective Agents; D002392:Catechin; D006861:Hydrogen Peroxide; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3; C057580:gallocatechol