title: The neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells.
abstract: Endoplasmic reticulum (ER) proteins including protein disulfide isomerase (PDI) are playing crucial roles in maintaining appropriate protein folding. Under nitrosative stress, an excess of nitric oxide (NO) radical species induced the S-nitrosylation of PDI cysteines which eliminate its isomerase and oxidoreductase capabilities. In addition, the S-nitrosylation-PDI complex is the cause of aggregation especially of the α-synuclein (α-syn) protein (accumulation of Lewy-body aggregates). We recently identified a potent antioxidant small molecule, Ferrostatin-1 (Fer-1), that was able to inhibit a non-apoptotic cell death named ferroptosis. Ferroptosis cell death involved the generation of oxidative stress particularly lipid peroxide. In this work, we reported the neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells (SH-SY5Y). We first synthesized the Fer-1 and confirmed that it is not toxic toward the SH-SY5Y cells at concentrations up to 12.5 μM. Second, we showed that Fer-1 compound quenched the commercially available stable radical, the 2,2-diphenyl-1-picrylhydrazyl (DPPH), in non-cellular assay at 82 %. Third, Fer-1 inhibited the ROS/RNS generated under rotenone insult in SH-SY5Y cells. Fourth, we revealed the effective role of Fer-1 in ER stress mediated activation of apoptotic pathway. Finally, we reported that Fer-1 mitigated rotenone-induced α-syn aggregation.
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: Parijat
authors.initials: P
authors.lastname: Kabiraj
authors.affiliation: Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Valenzuela
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Marin
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ramirez
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Mendez
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hwang
authors.affiliation: Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramirez
authors.affiliation: Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Fenelon
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA. mnarayan@utep.edu.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Narayan
authors.affiliation: Department of Chemistry, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79968, USA. rskouta@utep.edu.
authors.forename: Rachid
authors.initials: R
authors.lastname: Skouta
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003514:Cyclohexylamines / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010655:Phenylenediamines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity
chemical_list: D003514:Cyclohexylamines; D018696:Neuroprotective Agents; D010655:Phenylenediamines; D017382:Reactive Oxygen Species; C573944:ferrostatin-1; D012402:Rotenone; D009569:Nitric Oxide; D004298:Dopamine
keywords: Apoptosis; Endoplasmic reticulum stress; Ferrostatin-1; Inducible nitric oxide synthase; Oxidative stress; Protein disulfide isomerase (PDI); Rotenone; SH-SY5Y dopaminergic neuroblastoma cells; α-synuclein