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ID 32936
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Author
Fujita, Hirofumi Kaken ID researchmap
Shiosaka, Masahiko
Okimura, Yuya
Utsumi, Toshihiko
Sato, Eisuke F.
Akagi, Reiko
Inoue, Masayasu
Utsumi, Kozo
Abstract

We previously reported that the generation of reactive oxygen species (ROS) is the initial event in cell death induced by 6-hydroxydopamine (6-OHDA), an experimental model of Parkinsonism. Since recent studies suggested the important role of antioxidant activity of alpha-lipoic acid (LA) in the suppression of apoptosis of various types, we studied the effect on 6-OHDA-induced apoptosis of PC12 cells. Biochemical analysis revealed that LA suppressed the 6-OHDA-induced ROS generation, increase of caspase-like activity and chromatin condensation. The suppression of 6-OHDA-induced apoptosis by LA required pre-incubation of PC12 cells with LA for 12-24 h. LA increased the intracellular levels of heme oxygenase-1 (HO-1) and glutathione (GSH) and stimulated the expression of GSH synthesis-related genes such as cystine/glutamate antiporter and gamma-glutamylcysteine synthetase (gamma-GCS). However, Sn-mesoporphyrin IX, an inhibitor of HO-1, did not attenuate the LA-induced suppression of apoptosis. In contrast, buthionine sulfoximine, an inhibitor of gamma-GCS, attenuated the LA-induced suppression of ROS generation and chromatin condensation. in addition, a transcription factor Nrf2, which regulates the expression of antioxidant enzymes such as gamma-GCS, translocated to the nucleus by LA. These results suggested that LA suppressed the 6-OHDA induced-apoptosis by the increase in cellular glutathione through stimulation of the GSH synthesis system but not by the expression of HO-1.

Keywords
apoptosis
glutathione
gamma-glutamylcysteine synthetase; heme oxygenase-1
6-hydroxydopamine
alpha-lipoic acid
Nrf2
Note
Published with permission from the copyright holder.
This is a author's copy,as published in Brain Research , 2008 Vol.1206 pp.1-12
Publisher URL: http://dx.doi.org/10.1016/j.brainres.2008.01.081
Direct access to Thomson Web of Science record
Copyright © 2008 by Elsevier B.V.
Published Date
2008-06-23
Publication Title
Brain Research
Volume
volume1206
Start Page
1
End Page
12
Content Type
Journal Article
language
英語
Refereed
True
DOI
Web of Science KeyUT
Submission Path
neuroscience/3