title: Succinobucol, a Lipid-Lowering Drug, Protects Against 3-Nitropropionic Acid-Induced Mitochondrial Dysfunction and Oxidative Stress in SH-SY5Y Cells via Upregulation of Glutathione Levels and Glutamate Cysteine Ligase Activity.
abstract: Succinobucol (succinyl ester of probucol) is a lipid-lowering compound with anti-inflammatory and antioxidant properties. Recent experimental evidence has highlighted the potential neuroprotective effects of succinobucol. In the present study, cultured neuroblastoma (SH-SY5Y) cells were used to investigate mechanisms mediating the potential protective effect of succinobucol against mitochondrial metabolic impairment and oxidative stress induced by 3-nitropropionic acid (3-NP), a succinate dehydrogenase inhibitor that has been used in experimental models of the Huntington disease (HD). 3-NP decreased cellular viability after 24 h of incubation. This decline in cellular viability was preceded by (i) reduced mitochondrial complex II activity, (ii) increased reactive species generation, (iii) decreased mitochondrial membrane potential (ΔΨm), and (iv) diminished glutathione (GSH) levels. Succinobucol pretreatment (6 days) significantly prevented 3-NP-induced loss of cellular viability, generation of reactive oxygen species, and decrease of ΔΨm. However, succinobucol pretreatment did not protect against 3-NP-induced inhibition of mitochondrial complex II activity, pointing to the mitigation of secondary events resultant from mitochondrial complex II inhibition. Succinobucol pretreatment (6 days) significantly increased (50 %) the levels of GSH in SH-SY5Y cells, and this event was paralleled by significant increases in glutamate cysteine ligase messenger RNA (mRNA) expression and activity (GCL; the first enzyme in the GSH biosynthesis). The present findings are the first to show that succinobucol increases GSH levels via upregulation of GCL activity (possibly through the activation of the nuclear (erythroid-derived 2)-related factor (Nrf2)/antioxidant response element (ARE) pathway), displaying protective effects against mitochondrial dysfunction-derived oxidative stress.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Trindade, Bloco C, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil. dirleise@yahoo.com.br.
authors.forename: Dirleise
authors.initials: D
authors.lastname: Colle
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Trindade, Bloco C, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.
authors.forename: Danúbia Bonfanti
authors.initials: DB
authors.lastname: Santos
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Trindade, Bloco C, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.
authors.forename: Juliana Montagna
authors.initials: JM
authors.lastname: Hartwig
authors.affiliation: Escola de Química e Alimentos, Universidade Federal do Rio Grande, Campus Santo Antônio da Patrulha, Rio Grande, RS, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Godoi
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Trindade, Bloco C, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.
authors.forename: Daiane Fátima
authors.initials: DF
authors.lastname: Engel
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Trindade, Bloco C, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.
authors.forename: Andreza Fabro
authors.initials: AF
authors.lastname: de Bem
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Braga
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Trindade, Bloco C, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil. marcelo.farina@ufsc.br.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
mesh_terms: D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects*; D011341:Probucol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011422:Propionates; D020011:Protective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D006873:Hydroquinones; D000960:Hypolipidemic Agents; D009574:Nitro Compounds; D011422:Propionates; D020011:Protective Agents; D012333:RNA, Messenger; D019328:Buthionine Sulfoximine; C018855:2-tert-butylhydroquinone; D005979:Glutathione Peroxidase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; C471047:succinobucol; D011341:Probucol; C015392:3-nitropropionic acid
keywords: 3-nitropropionic acid; Glutamate cysteine ligase; Glutathione; Mitochondrial dysfunction; Oxidative stress; Succinobucol