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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.

Titel:	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.
Autor/in / Beteiligte Person:	Colle, D ; Santos, DB ; Hartwig, JM ; Godoi, M ; Engel, DF ; de Bem AF ; Braga, AL ; Farina, M
Link:	Zum Volltext
Zeitschrift:	Molecular neurobiology, Jg. 53 (2016-03-01), Heft 2, S. 1280-1295
Veröffentlichung:	Clifton, NJ : Humana Press, c1987-, 2016
Medientyp:	academicJournal
ISSN:	1559-1182 (electronic)
DOI:	10.1007/s12035-014-9086-x
Schlagwort:	Buthionine Sulfoximine pharmacology Cell Death drug effects Cell Line, Tumor Cell Survival drug effects Glutamate-Cysteine Ligase genetics Glutathione Peroxidase metabolism Humans Hydroquinones pharmacology Mitochondria drug effects Nitro Compounds Probucol pharmacology Propionates Protective Agents pharmacology RNA, Messenger genetics RNA, Messenger metabolism Time Factors Glutamate-Cysteine Ligase metabolism Glutathione metabolism Hypolipidemic Agents pharmacology Mitochondria metabolism Oxidative Stress drug effects Probucol analogs & derivatives Up-Regulation drug effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Mol Neurobiol] 2016 Mar; Vol. 53 (2), pp. 1280-1295. <i>Date of Electronic Publication: </i>2015 Jan 27. MeSH Terms: Glutamate-Cysteine Ligase / metabolism ; Glutathione / metabolism ; Hypolipidemic Agents / pharmacology ; Mitochondria / metabolism ; Oxidative Stress / drug effects ; Probucol / analogs & derivatives ; Up-Regulation / *drug effects ; Buthionine Sulfoximine / pharmacology ; Cell Death / drug effects ; Cell Line, Tumor ; Cell Survival / drug effects ; Glutamate-Cysteine Ligase / genetics ; Glutathione Peroxidase / metabolism ; Humans ; Hydroquinones / pharmacology ; Mitochondria / drug effects ; Nitro Compounds ; Probucol / pharmacology ; Propionates ; Protective Agents / pharmacology ; RNA, Messenger / genetics ; RNA, Messenger / metabolism ; Time Factors References: J Neurosci. 2009 Mar 4;29(9):2824-32. 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(PMID: 22203369) Contributed Indexing: Keywords: 3-nitropropionic acid; Glutamate cysteine ligase; Glutathione; Mitochondrial dysfunction; Oxidative stress; Succinobucol Substance Nomenclature: 0 (Hydroquinones) ; 0 (Hypolipidemic Agents) ; 0 (Nitro Compounds) ; 0 (Propionates) ; 0 (Protective Agents) ; 0 (RNA, Messenger) ; 5072-26-4 (Buthionine Sulfoximine) ; C12674942B (2-tert-butylhydroquinone) ; EC 1.11.1.9 (Glutathione Peroxidase) ; EC 6.3.2.2 (Glutamate-Cysteine Ligase) ; GAN16C9B8O (Glutathione) ; J1J54V24R4 (succinobucol) ; P3CTH044XJ (Probucol) ; QY4L0FOX0D (3-nitropropionic acid) Entry Date(s): Date Created: 20150127 Date Completed: 20161213 Latest Revision: 20190831 Update Code: 20231215

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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.