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.
Copyright (c) 2008 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Biomarkers
-
Cell Line, Tumor
-
Coenzymes / metabolism
-
Coenzymes / pharmacology
-
Coenzymes / therapeutic use
-
DNA Damage / drug effects
-
DNA Damage / physiology
-
Dose-Response Relationship, Drug
-
Drug Administration Schedule
-
Drug Synergism
-
Electron Transport Complex I / drug effects
-
Electron Transport Complex I / metabolism
-
Heat-Shock Proteins / drug effects
-
Heat-Shock Proteins / metabolism
-
Humans
-
Membrane Potential, Mitochondrial / drug effects
-
Membrane Potential, Mitochondrial / physiology
-
Mitochondria / drug effects*
-
Mitochondria / metabolism
-
Mitochondrial Diseases / drug therapy*
-
Mitochondrial Diseases / metabolism
-
Mitochondrial Diseases / physiopathology
-
Models, Biological
-
Nerve Tissue Proteins / drug effects
-
Nerve Tissue Proteins / metabolism
-
Oxidative Stress / drug effects*
-
Oxidative Stress / physiology
-
Oxygen Consumption / drug effects
-
Oxygen Consumption / physiology
-
Parkinson Disease / drug therapy*
-
Parkinson Disease / metabolism
-
Parkinson Disease / physiopathology
-
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
-
Reactive Oxygen Species / antagonists & inhibitors
-
Reactive Oxygen Species / metabolism
-
Rotenone / antagonists & inhibitors
-
Rotenone / toxicity
-
Transcription Factors / drug effects
-
Transcription Factors / metabolism
-
Ubiquitin / antagonists & inhibitors
-
Ubiquitin / metabolism
-
Uncoupling Agents / antagonists & inhibitors
-
Uncoupling Agents / toxicity
-
Vitamin B Complex / metabolism
-
Vitamin B Complex / pharmacology*
-
Vitamin B Complex / therapeutic use
-
alpha-Synuclein / antagonists & inhibitors
-
alpha-Synuclein / metabolism
Substances
-
Biomarkers
-
Coenzymes
-
Heat-Shock Proteins
-
Nerve Tissue Proteins
-
PPARGC1A protein, human
-
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
-
Reactive Oxygen Species
-
Transcription Factors
-
Ubiquitin
-
Uncoupling Agents
-
alpha-Synuclein
-
Rotenone
-
Vitamin B Complex
-
Electron Transport Complex I