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KMID : 0941820030130010029
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Korean Journal of Clinical Pharmacy
2003 Volume.13 No. 1 p.29 ~ p.39
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Effect of Epigallocatechin Gallate on Phosphoinositide 3-kinase/Akt and Glycogen Synthase Kinase-3 Pathway in Oxidative-stressed N18D3 Cells Following H_2O_2 Exposure
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Koh Seong-Ho
Kwon Hyug-Sung
Oh Hwa-Soon
Oh Jae-Ho
Park Youn-Joo
Kim Jun-Gyou
Kim Ki-Sok
kim Yong-Soon
Yang Ki-Hwa
Kim Seung-Up
Kim Seung-Hyun
Jung Hai-Kwan
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Abstract
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Neurodegenerative disorders are associated with apoptosis as a causing factor or an inducer. On the other hand, it has been reported that epigallocatechin gallate (EUG), one of antioxidants and flavonoids, and z-VAD-fmk, a nonselective caspase inhibitor, suppress oxidative-radical-stress-induced apoptosis. However, it is not yet known what is the effects of EGCG and z-VAD-fmk on the apoptotic pathway is through phosphoinositide 3-kinase (PI3K), Akt and glycogen synthase kinase-3 (GSK-3) as well as mitochondria, caspase-3 and poly (ADP-ribose) polymerase (PARP). We investigated the effects of EGCG by using H_2O_2 treated N18D3 cells, mouse DRG hybrid neurons. Methods: Following 30 min 100;{mu}m;H_2O_2 exposure, the viability of N18D3 cells (not pretreated vs. EGCG or z-VAD-fmk pretreated) was evaluated by using MTT assay. The effect of EGCG on immunoreactivity (IR) of cytochrome c, caspase-3, PARP, PI3K/Akt and GSK-3 was examined by using Western blot, and was compared with that of z-Y4D-fmk. Results: EGCG or z-VAD-fmk pretreated N18D3 cells showed increased viability. Dose-dependent inhibition of caspase-3 activation accompanied by PARP cleavage were demonstrated by pretreatment of both agents. However, inhibition of cytochrome c release was only detected in EGCG pretreated N18D3 cells. On the pathway through PI3K/Akt and GSK-3, however, the result of Western blot in EGCG pretreated N18D3 cells showed decreased IR of Akt and GSK-3 and increased IR of p85a PI3K, phosphorylated Akt and GSK-3, and contrasted with that in z-VAD-fmk pretreated N18D3 cells showing no changes on each molecule. Conclusion: These data show that EGCG affects apoptotic pathway through upstream signal including PI3K/Akt and GSK-3 pathway as well as downstream signal including cytochrome c and caspase-3 pathway. Therefore, these results suggest that EGCG mediated activation of PI3K/Akt and inhibition GSK-B could be new potential therapeutic strategy for neurodegenerative diseases associated with oxidative injury.
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KEYWORD
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Apoptosis, Neurodegenerative disease, Antioxidants, GSK-3, PI3K, Akt
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