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

Hirofumi Fujita, Masahiko Shiosaka, Tetsuya Ogino, Yuya Okimura, Toshihiko Utsumi, Eisuke F. Sato, Reiko Akagi, Masayasu Inoue, Kozo Utsumi, Junzo Sasaki

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalBrain Research
Volume1206
DOIs
Publication statusPublished - Apr 24 2008

Fingerprint

Thioctic Acid
Heme Oxygenase-1
Oxidopamine
Glutathione
Reactive Oxygen Species
Apoptosis
PC12 Cells
Chromatin
Antioxidants
Glutamate-Cysteine Ligase
Buthionine Sulfoximine
Antiporters
Cystine
Parkinsonian Disorders
Caspases
Glutamic Acid
Cell Death
Transcription Factors
Theoretical Models

Keywords

  • α-lipoic acid
  • γ-glutamylcysteine synthetase
  • 6-Hydroxydopamine
  • Apoptosis
  • Glutathione
  • Heme oxygenase-1
  • Nrf2

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

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. / Fujita, Hirofumi; Shiosaka, Masahiko; Ogino, Tetsuya; Okimura, Yuya; Utsumi, Toshihiko; Sato, Eisuke F.; Akagi, Reiko; Inoue, Masayasu; Utsumi, Kozo; Sasaki, Junzo.

In: Brain Research, Vol. 1206, 24.04.2008, p. 1-12.

Research output: Contribution to journalArticle

Fujita, Hirofumi ; Shiosaka, Masahiko ; Ogino, Tetsuya ; Okimura, Yuya ; Utsumi, Toshihiko ; Sato, Eisuke F. ; Akagi, Reiko ; Inoue, Masayasu ; Utsumi, Kozo ; Sasaki, Junzo. / 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. In: Brain Research. 2008 ; Vol. 1206. pp. 1-12.
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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

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KW - Heme oxygenase-1

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