Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease

Cassarino, David S.; Fall, Christopher P.; Swerdlow, Russell H.; Smith, Trisha S.; Halvorsen, Erik M; Miller, Scott W.; Parks, Janice P; Parker, W. Davis; Bennett, James P.

doi:10.1016/s0925-4439(97)00070-7

Cited by 244 publications

(162 citation statements)

References 65 publications

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“…SOD-catalase (100 and 150 U/ml, respectively) were added at the same time with rotenone and LPS. Seven days later, neurotoxicity was determined by PD have derived from postmortem analyses of PD brains in which microglial activation, elevated levels of proinflammatory mediators such as TNF␣, IL-1␤, and NO, and evidence of ROS production have been detected in the substantia nigra (McGeer et al, 1988;Cassarino et al, 1997;Hunot et al, 1999;Nagatsu et al, 2000). However, it is not clear whether these inflammatory "footprints" observed in the late stages of the pathogenesis of PD may merely be a reflection of reactive gliosis after the occurrence of the initial neuronal injuries.…”

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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“…Although the origin is unclear, oxidative stress has been thought to play a role in its pathogenesis [171][172][173], and the condition can be recapitulated experimentally by administration of MPTP (1,2,3,6-tetrahydropyridine), which results in increased ROS by inhibiting mitochondrial respiration and by activating Nox2 in microglia [171]. While defects in mitochondrial Complex I may underlie sporadic PD, activated or induced Nox enzymes in microglia may play a synergistic role [174].…”

Section: Nox Enzymes and Parkinson's Diseasementioning

confidence: 99%

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

578

448

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“…The finding of microglial clustering around senile plaques demonstrated that microglia are trying to phagocytose and remove toxic A plaques. However, microglia are known to produce many cytotoxic agents including proteolytic enzymes, cytokines, excitatory amino acids, quinolinic acid, complement proteins, reactive oxygen intermediates, and nitric oxide (Chao et al, 1992;Cassarino et al, 1997;McGuire et al, 2001;Liu et al, 2002). In addition, A can not only recruit and induce phagocytic activity of microglia, but also synthetic A also can induce the secretion of these cytotoxic agents (Meda et al, 1995;Sasaki et al, 1997).…”

Section: Admentioning

confidence: 99%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

572

443

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Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1β, TNF-α, IL-6), NO, PGE2, and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

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Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease

Cited by 244 publications

References 65 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

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

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