title: Upregulation of cellular glutathione by 3H-1,2-dithiole-3-thione as a possible treatment strategy for protecting against acrolein-induced neurocytotoxicity.
abstract: Acrolein, an unsaturated aldehydic product of lipid peroxidation, has been implicated in the pathogenesis of various neurodegenerative disorders including Parkinson's disease. However, protection against acrolein toxicity in neuronal cells via chemical upregulation of cellular aldehyde-detoxification factors has not been investigated. In this study, we have investigated the induction of glutathione (GSH), GSH S-transferase (GST), and aldose reductase (AR) by the unique nutraceutical compound 3H-1,2-dithiole-3-thione (D3T); and the protective effects of the D3T-mediated cellular defenses on acrolein-mediated toxicity in human neuroblastoma SH-SY5Y cells. Incubation of SH-SY5Y cells with D3T (10-100 microM) resulted in a marked concentration- and time-dependent induction of GSH, but not GST or AR. D3T treatment also led to increased mRNA expression of gamma-glutamylcysteine ligase (GCL), the key enzyme in GSH biosynthesis. Incubation of SH-SY5Y cells with 40 microM acrolein for 0.5 or 1 h resulted in a significant depletion of cellular GSH, which preceded the decrease of cell viability, suggesting critical involvement of GSH in acrolein-induced cytotoxicity. Pretreatment of SH-SY5Y cells with 100 microM D3T afforded a dramatic protection against acrolein-induced cytotoxicity, as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) reduction, lactate dehydrogenase release, as well as morphological changes. To further demonstrate the involvement of GSH in protection against acrolein-induced cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. Depletion of cellular GSH by 25 microM BSO dramatically potentiated acrolein-induced cytotoxicity. Cotreatment of SH-SY5Y cells with BSO and D3T was found to prevent the D3T-mediated GSH induction and completely reverse the cytoprotective effects of D3T on acrolein-induced toxicity. Taken together, this study demonstrates that upregulation of GSH is a predominant mechanism underlying D3T-mediated protection against acrolein-induced neurocytotoxicity.
authors.affiliation: Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, 2265 Kraft Drive, Blacksburg, VA 24060, USA.
authors.forename: Zhenquan
authors.initials: Z
authors.lastname: Jia
authors.forename: Bhaba R
authors.initials: BR
authors.lastname: Misra
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Li
authors.forename: Hara P
authors.initials: HP
authors.lastname: Misra
mesh_terms: D000171:Acrolein / Q000633:toxicity*; D000449:Aldehyde Reductase / Q000096:biosynthesis; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004790:Enzyme Induction; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D005978:Glutathione / Q000096:biosynthesis* / Q000187:drug effects; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D013871:Thiones; D013876:Thiophenes; D019328:Buthionine Sulfoximine; D000171:Acrolein; D000449:Aldehyde Reductase; D007770:L-Lactate Dehydrogenase; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; C049325:1,2-dithiol-3-thione