α-Lipoic acid suppresses 6-hydroxydopamine-induced ROS generation and apoptosis through the stimulation of glutathione synthesis but not by the expression of heme oxygenase-1
- 作者：Hirofumi Fujita ; Masahiko Shiosaka ; Tetsuya Ogino ; Yuya Okimura ; Toshihiko Utsumi ; Eisuke F. Sato ; Reiko Akagi ; Masayasu Inoue ; Kozo Utsumi ; Junzo Sasaki
- 关键词：Apoptosis ; Glutathione ; γ ; -glutamylcysteine synthetase ; Heme oxygenase-1 ; 6-Hydroxydopamine ;
//www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">-lipoic acid
- 刊名：Brain Research
- 出版年：2008
- 期刊代码：8_00068993
- 类别：neu
- 出版时间：24 April 2008
- 卷：1206
- 期：Complete
- 页码：1-12
- 文件大小：1096 K
摘要
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 
-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 γ-glutamylcysteine synthetase (γ-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 γ-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 γ-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.
-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 γ-glutamylcysteine synthetase (γ-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 γ-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 γ-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.