title: Synergistic anti-Parkinsonism activity of high doses of B vitamins in a chronic cellular model.
abstract: We propose that elevation of mitochondrial enzyme cofactors may prevent or ameliorate neurodegenerative diseases by improving mitochondrial function. In the present study, we investigated the effects of high doses of B vitamins, the precursors of mitochondrial enzyme cofactors, on mitochondrial dysfunction, oxidative stress, and Parkinsonism in a 4-week long rotenone treatment-induced cellular model of Parkinson's disease (PD). Pretreatment with B vitamins (also 4 weeks) prevented rotenone-induced: (1) mitochondrial dysfunction, including reduced mitochondrial membrane potential and activities of complex I; (2) oxidative stress, including increase in reactive oxygen species, oxidative DNA damage and protein oxidation, and (3) Parkinsonism parameters, including accumulation of alpha-synuclein and poly-ubiquitin. The optimum doses were found around 2.5- and 5-fold of that in normal MEM medium. The 4-week pretreatment was chosen based on time-dependent experiments that pretreatments longer than 2 weeks resulted in a decrease in oxidants, an increase in oxygen consumption, and up-regulation of complex I activity and PGC-1alpha expression. Individual B vitamins at the same doses did not show a similar effect suggesting that these B vitamins work synergistically. These results suggest that administration of high doses of B vitamins sufficient to elevate mitochondrial enzyme cofactors may be effective in preventing PD by reducing oxidative stress and improving mitochondrial function.
authors.affiliation: Institute for Nutritional Science, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Haiqun
authors.initials: H
authors.lastname: Jia
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
authors.forename: Jiejie
authors.initials: J
authors.lastname: Hao
authors.forename: Xuesen
authors.initials: X
authors.lastname: Li
authors.forename: Weili
authors.initials: W
authors.lastname: Shen
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D015415:Biomarkers; D045744:Cell Line, Tumor; D003067:Coenzymes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012402:Rotenone / Q000037:antagonists & inhibitors / Q000633:toxicity; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000378:metabolism; D014475:Uncoupling Agents / Q000037:antagonists & inhibitors / Q000633:toxicity; D014803:Vitamin B Complex / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D015415:Biomarkers; D003067:Coenzymes; D006360:Heat-Shock Proteins; D009419:Nerve Tissue Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D025801:Ubiquitin; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D012402:Rotenone; D014803:Vitamin B Complex; D042967:Electron Transport Complex I