The Role of NADPH Oxidase 1–Derived Reactive Oxygen Species in Paraquat-Mediated Dopaminergic Cell Death

Cristóvão, Ana Clara; Choi, Dong Hee; Baltazar, Graça; Beal, M. Flint; Kim, Yoon Seong

doi:10.1089/ars.2009.2459

Cited by 143 publications

(88 citation statements)

References 61 publications

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“…This is consistent with the reports suggesting that loss of reduced glutathione with a concomitant inhibition of mitochondrial thiol homeostasis lead to mitochondrial dysfunction and increased iron accumulation by modulating iron regulating proteins to cause oxidative stress-induced neurodegeneration (9,12). NADPH oxidase 1, a specialized superoxide generating system and Rac1, one of its active component found in midbrain dopaminergic neurons, has emerged as a new player in mediating neurodegeneration via oxidative damage (4). Accordingly, the discovery of novel strategies to mitigate oxidative stress has been a principal focus of current therapeutic initiatives.…”

Section: Thomassupporting

confidence: 91%

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Thomas

2009

Antioxidants & Redox Signaling

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Parkinson's disease (PD) is a complex multifactor disease marked by extensive neuropathology in the brain with selective yet prominent and progressive loss of midbrain dopamine neurons. Clinically PD is characterized by motor abnormalities including resting tremor, bradykinesia, altered gait, muscular rigidity, postural instability, together with autonomic dysfunctions. The etiological factors involved in the development of PD are still elusive, but there is considerable evidence that a combination of genetic susceptibilities and environmental factors plays a critical role in disease pathogenesis. The identification of single genes in the past decade linked to heritable forms of PD has challenged the previously held view of a nongenetic etiology for this progressive movement disorder. These genetic breakthroughs have revolutionized the research by providing unique opportunities to pursue novel mechanisms and identified new clues to disease pathogenesis in PD. This forum review provides an update on current hypotheses and recent findings in mitochondrial dysfunction, oxidative damage, innate and adaptive immune systems, protein misfolding and aggregation, and advances in translational approaches to PD. These aspects are reviewed with an aim to promote better understanding of molecular pathways prevalent in parkinsonian brain that will eventually aide in development of promising therapeutic strategies.

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Section: Thomassupporting

confidence: 91%

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Thomas

2009

Antioxidants & Redox Signaling

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“…Although the expression of this enzyme has been well documented in microglia, it is also present in astrocytes (30) and DA neurons (31). In mice deficient in gp91 phox (a functional subunit required by NADPH oxidase), PQ 2+ failed to induced neurotoxicity (29,32).…”

Section: Discussionmentioning

confidence: 99%

Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3

Rappold

Cui

Chesser

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

167

156

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The herbicide paraquat (PQ) has increasingly been reported in epidemiological studies to enhance the risk of developing Parkinson's disease (PD). Furthermore, case-control studies report that individuals with genetic variants in the dopamine transporter (DAT, SLC6A) have a higher PD risk when exposed to PQ. However, it remains a topic of debate whether PQ can enter dopamine (DA) neurons through DAT. We report here a mechanism by which PQ is transported by DAT: In its native divalent cation state, PQ 2+ is not a substrate for DAT; however, when converted to the monovalent cation PQ + by either a reducing agent or NADPH oxidase on microglia, it becomes a substrate for DAT and is accumulated in DA neurons, where it induces oxidative stress and cytotoxicity. Impaired DAT function in cultured cells and mutant mice significantly attenuated neurotoxicity induced by PQ + . In addition to DAT, PQ + is also a substrate for the organic cation transporter 3 (Oct3, Slc22a3), which is abundantly expressed in non-DA cells in the nigrostriatal regions. In mice with Oct3 deficiency, enhanced striatal damage was detected after PQ treatment. This increased sensitivity likely results from reduced buffering capacity by non-DA cells, leading to more PQ + being available for uptake by DA neurons. This study provides a mechanism by which DAT and Oct3 modulate nigrostriatal damage induced by PQ 2+ /PQ + redox cycling.neurodegeneration | extraneuronal monoamine transporter | astrocytes | in vivo microdialysis P arkinson's disease (PD) is characterized primarily by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (1). Although in past decades discoveries of genetic mutations linked to PD have significantly impacted our current understanding of the pathogenesis of this devastating disorder, it is likely that the environment plays a critical role in the etiology of sporadic PD. Human epidemiological studies indicate that exposure to herbicides, pesticides, and heavy metals increase the risk of PD. One such environmental toxicant is paraquat (PQ 2+ , N,N′-dimethyl-4-4′-bipiridinium) (2, 3). This molecule exists natively as a divalent cation, but can undergo redox cycling with cellular diaphorases such as NADPH oxidase and nitric oxide synthase (4) (NOS) to yield the monovalent cation PQ + . From this redox cycle, superoxide is generated, leading to oxidative stress-related cytotoxicity. (For clarity and brevity, the abbreviations PQ 2+ and PQ + will be used to signify the respective cations, whereas PQ represents a general term when the valency is ambiguous.) On the basis of its structural similarity to 1-methyl-4-phenylpyridinium (MPP + ), an active metabolite of the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (5), PQ 2+ has been predicted to be a potential environmental parkinsonian toxicant (6), and with subsequent recent epidemiological studies (2, 3), there has been increasing interest in this herbicide as a potential pathogenic agent in PD.When PQ 2+ is injected into mice, it induces a ...

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“…Several inhibitors of NADPH oxidase have been tested for their anti-inflammatory and antioxidant effects in dopaminergic cells, including apocynin (4-hydroxy-3-methoxyacetophenone), a non-toxic plant-derived molecule that is well-tolerated in cell culture and animals models of PD (Gao et al, 2003a; Anantharam et al, 2007; Cristovao et al, 2009). We recently demonstrated diapocynin to be neuroprotective and anti-neuroinflammatory in the MPTP animal model as well as in the progressively degenerative LRRK2 R1441G transgenic mouse model (Ghosh et al, 2012b; Dranka et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

Ghosh

Langley

Harischandra

et al. 2016

J Neuroimmune Pharmacol

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Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.

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The Role of NADPH Oxidase 1–Derived Reactive Oxygen Species in Paraquat-Mediated Dopaminergic Cell Death

Cited by 143 publications

References 61 publications

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

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