Potent Upregulation of Glutathione and NAD(P)H:Quinone Oxidoreductase 1 by Alpha-lipoic Acid in Human Neuroblastoma SH-SY5Y Cells: Protection Against Neurotoxicant-elicited Cytotoxicity |
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Authors: | Zhenquan Jia Seema Hallur Hong Zhu Yunbo Li Hara P Misra |
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Institution: | (1) Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Research Building II, 1861 Pratt Drive, Blacksburg, VA 24060, USA;(2) Department of Pharmaceutical Sciences, St. John’s University College of Pharmacy and Allied Health Professions, Queens, NY 11439, USA |
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Abstract: | Alpha-lipoic acid (LA) has recently been reported to afford protective effects in neurodegenerative disorders. However, the
mechanisms underlying LA-mediated neuroprotection remain to be investigated. This study was undertaken to determine whether
LA treatment could increase endogenous antioxidants and phase 2 enzymes in cultured human neuroblastoma SH-SY5Y cells, and
whether such increased cellular defenses could afford protection against cytotoxicity induced by neurotoxicants. Incubation
of SH-SY5Y cells with micromolar concentrations of LA for 24 h resulted in a significant increase in the levels of reduced
glutathione (GSH) and NAD(P)H:quinone oxidoreductase 1 (NQQ1) in a concentration-dependent fashion. Treatment of the cells
with LA also led to an increased mRNA expression of γ-glutamylcysteine ligase catalytic subunit (GCLC) and NQO1. To determine
the protective effects of the LA-induced cellular defenses on neurotoxicant-elicitedl cell injury, SH-SY5Y cells were pretreated
with LA for 24 h and then exposed to acrolein, 4-hydroxy-2-nonenal (HNE), H2O2 and the peroxynitrite generator, 3-morpholinosydnonimine (SIN-1). We observed that LA pretreatment of SH-SY5Y cells led to
a marked protection against acrolein, HNE, H2O2 and SIN-1-mediated cytotoxicity, as detected by 3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. Taken
together, this study demonstrates for the first time that LA can induce GSH and NQO1 in cultured human neuroblastoma cells
and LA-upregulated cellular defenses are accompanied by a markedly increased resistance to cytotoxicity induced by various
neurotoxicants. The results of this study may have important implications for the neuroprotective effects of LA. |
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Keywords: | SH-SY5Y cells Alpha-lipoic acid GSH NQO1 Antioxidants Acrolein HNE H2O2 SIN-1 Cytotoxicity |
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