title: Mechanisms of CDDO-imidazolide-mediated cytoprotection against acrolein-induced neurocytotoxicity in SH-SY5Y cells and primary human astrocytes.
abstract: Acrolein is a ubiquitous unsaturated aldehyde has been implicated in the pathogenesis of various neurological disorders. However, limited study has been conducted into potential therapeutic protection and underlying mechanism against acrolein-induced cytotoxicity via upregulation of cellular aldehyde-detoxification defenses. In this study we have utilized RA-differentiated human SH-SY5Y cells and primary human astrocytes to investigate the induction of glutathione (GSH) by the synthetic triterpenoid 2-cyano-3,12-dixooleana-1,9-dien-28-imidazolide (CDDO-Im) and the protective effects CDDO-Im-mediated antioxidant defenses on acrolein toxicity. Acrolein exposure to RA-differentiated SH-SY5Y cells resulted in a significant time dependent depletion of cellular GSH preceding a reduction in cell viability and LDH release. Further, we demonstrated the predominance of cellular GSH in protection against acrolein-induced cytotoxicity. Buthionine sulfoximine (BSO) at 25μM dramatically depleted GSH and significantly potentiated acrolein-induced cytotoxicity. Pretreatment of the cells with 100nM CDDO-Im afforded a dramatic protection against acrolein-induced cytotoxicity. Pretreatment of BSO and CDDO was found to prevent the CDDO-Im-mediated GSH induction and partially reversed the cytoprotective effects of CDDO-Im against acrolein cytotoxicity. Overall, this study represents for the first time the CDDO-Im mediated upregulation of GSH is a predominant mechanism against acrolein-induced neurotoxicity.
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Speen
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Colton
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Ruby
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Halley
authors.initials: H
authors.lastname: Shah
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Nallasamy
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Elizabeth A S
authors.initials: EA
authors.lastname: Brooke
authors.affiliation: Department of Pharmacology, Campbell University, School of Osteopathic Medicine, Buies Creek, NC 27506, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA; Department of Pharmacology, Campbell University, School of Osteopathic Medicine, Buies Creek, NC 27506, USA; Virginia Tech-Wake Forest University School of Biomedical Engineers and Sciences, Blacksburg, VA 24061, USA; Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Electronic address: yli@campbell.edu.
authors.forename: Y Robert
authors.initials: YR
authors.lastname: Li
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA. Electronic address: z_jia@uncg.edu.
authors.forename: Zhenquan
authors.initials: Z
authors.lastname: Jia
mesh_terms: D000171:Acrolein / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D009828:Oleanolic Acid; D000171:Acrolein; D007770:L-Lactate Dehydrogenase; D005978:Glutathione
keywords: Acrolein; Aldose reductase; CDDO-Im; Cytoprotection; Glutathione; Primary human astrocytes; Retinoic acid—differentiated human SH-SY5Y cells