1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles

Hasegawa, Eiji; Takeshige, Koichiro; Oishi, Toshihide; Murai, Yoshiyuki; Minakami, Shigeki

doi:10.1016/0006-291x(90)90498-c

Cited by 321 publications

(163 citation statements)

References 26 publications

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“…In addition, ROS such as superoxide can react with reactive nitrative species such as NO to form more reactive intermediates such as peroxynitrite. Furthermore, it has been proposed that extracellular ROS may promote the mitochondria-mediated generation of intracellular ROS (Hasegawa et al, 1990). In the brain, at least for rodents, the midbrain region, which encompasses the substantia nigra, is particularly rich in microglia (Lawson et al, 1990;Kim et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

et al. 2003

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Parkinson's disease (PD) is characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway resulting in movement disorders. Although its etiology remains unknown, PD may be the final outcome of interactions among multiple factors, including exposure to environmental toxins and the occurrence of inflammation in the brain. In this study, using primary mesencephalic cultures, we observed that nontoxic or minimally toxic concentrations of the pesticide rotenone (0.5 nM) and the inflammogen lipopolysaccharide (LPS) (0.5 ng/ml) synergistically induced dopaminergic neurodegeneration. The synergistic neurotoxicity of rotenone and LPS was observed when the two agents were applied either simultaneously or in tandem. Mechanistically, microglial NADPH oxidase-mediated generation of reactive oxygen species appeared to be a key contributor to the synergistic dopaminergic neurotoxicity. This conclusion was based on the following observations. First, inhibition of NADPH oxidase or scavenging of free radicals afforded significant neuroprotection. Second, rotenone and LPS synergistically stimulated the NADPH oxidase-mediated release of the superoxide free radical. Third and most importantly, rotenone and LPS failed to induce the synergistic neurotoxicity as well as the production of superoxide in cultures from NADPH oxidase-deficient animals. This is the first demonstration that low concentrations of a pesticide and an inflammogen work in synergy to induce a selective degeneration of dopaminergic neurons. Findings from this study may be highly relevant to the elucidation of the multifactorial etiology of PD and the discovery of effective therapeutic agents for the treatment of the disease.

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Section: Discussionmentioning

confidence: 99%

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

et al. 2003

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“…Widespread examples are the reduction of tetrazolium salts for formazan [34], the reduction of ferricytochrome C [35]. Other chromogens used are epinephrine [36,37] or adrenaline [38] for O 2 •-. These methods are still useful in some specific experimental situations.…”

Section: Spectrophotometric Methodsmentioning

confidence: 99%

Determination of mitochondrial reactive oxygen species: methodological aspects

Batandier

Fontaine

Kériel

et al. 2002

J Cellular Molecular Medi

138

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The generation of Reactive Oxygen Species (ROS) as by-products in mitochondria Electron Transport Chain (ETC) has long been admitted as the cost of aerobic energy metabolism with oxidative damages as consequence. The purpose of this methodological review is to present some of the most widespread methods of ROS generation and to underline the limitations as well as some problems, identified with some experiments as examples, in the interpretation of such results. There is now no doubt that besides their pejorative role, ROS are involved in a variety of cellular processes for the continuous adaptation of the cell to its environment. Because ROS metabolism is a complex area (low production, instability of species, efficient antioxidant defense system, several places of production…) bias, variances and limitations in ROS measurements must be recognized in order to avoid artefactual conclusions, and especially to improve our understanding of physiological and pathophysiological mechanisms of such phenomenon.

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“…PD is also associated with exposure to pesticides (3, 4), many of which are either oxidants or mitochondrial toxins. Rapid onset of Parkinsonism in young adults following injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5) occurs through its active metabolite, 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I (6), potentially by depleting energy stores and inducing oxidative stress (7,8).Complex I is specifically and irreversibly inhibited by the neurotoxin rotenone, a hydrophobic pesticide epidemiologically linked to PD. Continuous, systemic, in vivo infusion of 2-3 mg/kg/day rotenone in rats over weeks produces relatively selective nigrostriatal dopaminergic neurodegeneration, with formation of ubiquitin-and ␣-synuclein-positive inclusions (9, 10).…”

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confidence: 99%

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confidence: 99%

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Kweon¹,

Marks²,

Krencik³

et al. 2004

Journal of Biological Chemistry

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The pathogenesis underlying the selective degeneration of dopaminergic neurons in Parkinson's disease (PD) 1 is not fully defined, but multiple lines of evidence implicate mitochondrial dysfunction. Thus, defects in complex I of the mitochondrial respiratory chain in the substantia nigra and evidence of oxidative stress have been noted in the brains of PD patients (1, 2). PD is also associated with exposure to pesticides (3, 4), many of which are either oxidants or mitochondrial toxins. Rapid onset of Parkinsonism in young adults following injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5) occurs through its active metabolite, 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I (6), potentially by depleting energy stores and inducing oxidative stress (7,8).Complex I is specifically and irreversibly inhibited by the neurotoxin rotenone, a hydrophobic pesticide epidemiologically linked to PD. Continuous, systemic, in vivo infusion of 2-3 mg/kg/day rotenone in rats over weeks produces relatively selective nigrostriatal dopaminergic neurodegeneration, with formation of ubiquitin-and ␣-synuclein-positive inclusions (9, 10). This low dose paradigm results in about 75% inhibition of complex I activity, and corresponds to a brain concentration of 20 -30 nM (9, 10). However, although these studies establish the principle that complex I dysfunction leads to degeneration in dopaminergic neurons, consistent levels of functional deficits related to complex I dysfunction have been difficult to reproduce (11). Accordingly, this in vivo model has not lent itself easily to the study of the mechanism of rotenone toxicity (12). Similarly, the use of primary cultures of dopaminergic neurons to study mechanisms of rotenone-induced neurodegeneration has been limited: short term, nanomolar rotenone administration in primary cultures of dopaminergic neurons does not produce selective dopaminergic damage (13). In addition, primary cultures contain a mixture of dopaminergic and nondopaminergic neurons and therefore do not lend themselves to molecular and biochemical analyses. The use of existing cell lines to study the effects of chronic rotenone exposure (14) also has shortcomings. Most cell lines do not exhibit robust dopaminergic phenotypes. In addition, the high rate of proliferation that characterize these cell lines confound the assessment of cellular susceptibility to rotenone, because proliferating cells may replace those that have succumbed to rotenone, and chronic exposure may lead to the selection of cells that become resistant to rotenone toxicity.To study the cellular mechanisms of rotenone-induced dopaminergic neuronal degeneration, we therefore developed a novel cellular model derived from immortalized midbrain MN9D cells (15), a dopaminergic neuronal cell line that has been extensively characterized as a model of dopaminergic neurons (16 -19). Using sodium butyrate (NaBu) (20) to differentiate MN9D cells and cells from a related, immortalized, non-dopaminergic midbrain neuronal cell line (MN9X ...

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1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles

Cited by 321 publications

References 26 publications

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

Determination of mitochondrial reactive oxygen species: methodological aspects

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

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