NADPH oxidase mediates oxidative stress in the L-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease

Department of Neurology, Columbia University, New York, NY 10032, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2003; 100(10):6145-50. DOI: 10.1073/pnas.0937239100
Source: PubMed


Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may contribute to MPTP- and PD-related neurodegeneration. However, whether inflammation may cause oxidative damage in MPTP and PD is unknown. Here we show that NADPH-oxidase, the main reactive oxygen species (ROS)-producing enzyme during inflammation, is up-regulated in SNpc of human PD and MPTP mice. These changes coincide with the local production of ROS, microglial activation, and DA neuronal loss seen after MPTP injections. Mutant mice defective in NADPH-oxidase exhibit less SNpc DA neuronal loss and protein oxidation than their WT littermates after MPTP injections. We show that extracellular ROS are a main determinant in inflammation-mediated DA neurotoxicity in the MPTP model of PD. This study supports a critical role for NADPH-oxidase in the pathogenesis of PD and suggests that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.

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    • "ed superoxide results in far more potent neuroprotective effects than antioxidants ( Block et al . , 2007 ; Gao et al . , 2012 ) . Supporting this notion , we and others have found that microglia - mediated neuroinflam - mation contributes to the progressive dopaminergic neurode - generation in PD patients and animal models ( Gao and Hong , 2008 ; Wu et al . , 2003 ) . Mechanistic studies revealed that NOX2 is a key mediator in the maintenance of microglia - mediated neuroinflammation ( Block and Hong , 2005 ; Block et al . , 2007 ; Brown , 2007 ; Levesque et al . , 2010 ) . Thus , NOX2 may be an optimal target for developing neurodegenerative disease - modifying drugs . Consistent with this conce"
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    ABSTRACT: Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinson's disease (PD). The inhibition of NOX2-generated superoxide has become an effective strategy for developing disease-modifying therapies for PD. However, the lack of specific and potent NOX2 inhibitors has hampered the progress of this approach. Diphenyleneiodonium (DPI) is a widely used, long-acting NOX2 inhibitor. However, due to its non-specificity for NOX2 and high cytotoxicity at standard doses (µM), DPI has been precluded from human studies. In this study, using ultra-low doses of DPI, we aimed to: (1) investigate whether these problems could be circumvented and (2) determine whether ultra-low doses of DPI were able to preserve its utility as a potent NOX2 inhibitor. We found that DPI at subpicomolar concentrations (10−14 and 10−13 M) displays no toxicity in primary midbrain neuron-glia cultures. More importantly, we observed that subpicomolar DPI inhibited phorbol myristate acetate (PMA)-induced activation of NOX2. The same concentrations of DPI did not inhibit the activities of a series of flavoprotein-containing enzymes. Furthermore, potent neuroprotective efficacy was demonstrated in a post-treatment study. When subpicomolar DPI was added to neuron-glia cultures pretreated with lipopolysaccharide, 1-methyl-4-phenylpyridinium or rotenone, it potently protected the dopaminergic neurons. In summary, DPI's unique combination of high specificity toward NOX2, low cytotoxicity and potent neuroprotective efficacy in post-treatment regimens suggests that subpicomolar DPI may be an ideal candidate for further animal studies and potential clinical trials. GLIA 2014
    Glia 12/2014; 62(12). DOI:10.1002/glia.22724 · 6.03 Impact Factor
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    • "Further support came from Przedborski et al. (1992), who demonstrated that overexpression of the copper–zinc form of superoxide dismutase (SOD) in mice is neuroprotective against the damaging effects of MPTP. Moreover, Wu et al. (2003), using the fluorescent tag hydroethidium, provided an in vivo demonstration of the presence of the superoxide radical in the MPTP neurotoxic process. NO, produced in the glial cells, can enter the cytosol of the neuron via simple membrane diffusion. "
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    ABSTRACT: Parkinson disease (PD) is the third most common neurodegenerative disorder affecting humans. Although it is clear that the etiology of a small number of PD cases is strictly genetic (either dominant or recessive) or purely environmental factors (e.g., pesticides, drug use, viruses, heavy metal exposure), it is likely that most cases arise from a combination of the two risk factors. For this reason, the generation and study of animal models where these interactions can be studied can provide important information regarding the pathophysiology of PD. In this chapter, we examine the mechanisms underlying xenobiotic-induced Parkinsonism using 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine as the model agent. We also examine other environmental agents that have been shown to induce Parkinsonism, including paraquat, lippopolysaccharide, and the highly pathogenic avian influenza virus.
    Movement Disorder. Genetics and models, Second edited by Mark LeDoux, 10/2014: pages 287-306; Elsevier., ISBN: 978-0-12-405195-9
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    • "NADPH oxidase (NOX) is one of the major enzymes involved in the process of oxidative stress. Its overexpression is induced especially by microglial activation in the brain in both acute (Block et al., 2007) and chronic conditions (Wu et al., 2003). NOX seems to play a role in AD, especially by the action of NOX2, which is upregulated in the brain of AD patients (Shimohama et al., 2000; Zekry et al., 2003). "

    Frontiers in Aging Neuroscience 07/2014; 6. DOI:10.3389/fnagi.2014.00206 · 4.00 Impact Factor
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