TY - JOUR
T1 - 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
AU - Fujita, Hirofumi
AU - Shiosaka, Masahiko
AU - Ogino, Tetsuya
AU - Okimura, Yuya
AU - Utsumi, Toshihiko
AU - Sato, Eisuke F.
AU - Akagi, Reiko
AU - Inoue, Masayasu
AU - Utsumi, Kozo
AU - Sasaki, Junzo
PY - 2008/4/24
Y1 - 2008/4/24
N2 - 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 α-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.
AB - 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 α-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.
KW - 6-Hydroxydopamine
KW - Apoptosis
KW - Glutathione
KW - Heme oxygenase-1
KW - Nrf2
KW - α-lipoic acid
KW - γ-glutamylcysteine synthetase
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UR - http://www.scopus.com/inward/citedby.url?scp=41649114315&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2008.01.081
DO - 10.1016/j.brainres.2008.01.081
M3 - Article
C2 - 18355802
AN - SCOPUS:41649114315
VL - 1206
SP - 1
EP - 12
JO - Molecular Brain Research
JF - Molecular Brain Research
SN - 0006-8993
ER -