Paraquat and maneb co-exposure induces noradrenergic locus coeruleus neurodegeneration through NADPH oxidase-mediated microglial activation

Hou, Liyan; Zhang, Cong; Wang, Ke; Liu, Xiaofang; Wang, Hongwei; Che, Yuning; Sun, Fuqiang; Zhou, Xueying; Zhao, Xianxian; Wang, Qingshan

doi:10.1016/j.tox.2017.02.009

Cited by 41 publications

(32 citation statements)

References 61 publications

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“…Male C57BL/6J mice (3-month old) were randomly divided into four groups, that is, control, P + M and taurine plus P + M groups ( n = 6–9 in each group). Mice in P + M group were administrated (i.p, 5 μl/g body weight) with combined paraquat (10 mg/kg) and maneb (30 mg/kg) for consecutive 6 weeks (twice per week) according to our previous report 49 . Mice in taurine plus P + M group were received with taurine (150 mg/kg, i.p, 5 μl/g body weight) 30 min before P + M co-exposure.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted by using RNAiso Plus and reverse transcribed with an oligodT primer according to our previous reports 49 , 53 . Real-time PCR amplification was performed using SYBR Premix Ex Taq TM II (Takara Bio Inc., Kusatsu, Shiga, Japan) and Takara Thermal Cycler Dice ™ Real Time System according to manufacturer’s protocols.…”

Section: Methodsmentioning

confidence: 99%

“…The PCR conditions were 95 °C for 10 s, 55 °C for 30 s and 72 °C for 30 s for 40 cycles. Relative mRNA gene levels were normalized to the GAPDH mRNA level and relative expression levels were determined by the comparative Ct method 49 . We set the mRNA abundance of vehicle group as 1 unit.…”

Section: Methodsmentioning

confidence: 99%

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Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization

et al. 2018

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Microglia-mediated neuroinflammation is implicated in multiple neurodegenerative disorders, including Parkinson’s disease (PD). Hence, the modulatioein of sustained microglial activation may have therapeutic potential. This study is designed to test the neuroprotective efficacy of taurine, a major intracellular free β-amino acid in mammalian tissues, by using paraquat and maneb-induced PD model. Results showed that mice intoxicated with paraquat and maneb displayed progressive dopaminergic neurodegeneration and motor deficits, which was significantly ameliorated by taurine. Taurine also attenuated the aggregation of α-synuclein in paraquat and maneb-intoxicated mice. Mechanistically, taurine suppressed paraquat and maneb-induced microglial activation. Moreover, depletion of microglia abrogated the dopaminergic neuroprotective effects of taurine, revealing the role of microglial activation in taurine-afforded neuroprotection. Subsequently, we found that taurine suppressed paraquat and maneb-induced microglial M1 polarization and gene expression levels of proinflammatory factors. Furthermore, taurine was shown to be able to inhibit the activation of NADPH oxidase (NOX2) by interfering with membrane translocation of cytosolic subunit, p47phox and nuclear factor-kappa B (NF-κB) pathway, two key factors for the initiation and maintenance of M1 microglial inflammatory response. Altogether, our results showed that taurine exerted dopaminergic neuroprotection through inactivation of microglia-mediated neuroinflammation, providing a promising avenue and candidate for the potential therapy for patients suffering from PD.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization

et al. 2018

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“…We previously reported that NOX2 is critical for chronic microglial activation. The production of NOX2-derived superoxide is the early event during microglial activation 47 . A variety of PD-related toxicants, such as rotenone, paraquat, and the fungicide maneb, can stimulate the release of NOX2-generated superoxide, which is associated with microglial activation and dopaminergic neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

2,5-Hexanedione induces dopaminergic neurodegeneration through integrin αMβ2/NADPH oxidase axis-mediated microglial activation

et al. 2018

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Recent study demonstrated that chronic exposure to solvents increases the risk of Parkinson’s disease (PD), the second most common neurodegenerative disorder characterized by progressive dopaminergic neurodegeneration in the substantia nigra (SN). n-Hexane, a widely used organic solvent, displays central-peripheral neurotoxicity, which is mainly mediated by its active metabolite, 2,5-hexanedione (HD). However, whether HD exposure contributes to PD remains unclear. In this study, we found that rats exposed to HD displayed progressive dopaminergic neurodegeneration in the nigrostriatal system. Microglial activation was also detected in HD-treated rats, which occurred prior to degeneration of dopaminergic neurons. Moreover, depletion of microglia markedly reduced HD-induced dopaminergic neurotoxicity. Mechanistic study revealed an essential role of microglial integrin αMβ2-NADPH oxidase (NOX2) axis in HD-elicited neurotoxicity. HD activated NOX2 by inducing membrane translocation of NOX2 cytosolic subunit, p47phox. Integrin αMβ2 was critical for HD-induced NOX2 activation since inhibition or genetic deletion of αMβ2 attenuated NOX2-generated superoxide and p47phox membrane translocation in response to HD. Src and Erk, two downstream signals of αMβ2, were recognized to bridge HD/αMβ2-mediated NOX2 activation. Finally, pharmacological inhibition of αMβ2-NOX2 axis attenuated HD-induced microglial activation and dopaminergic neurodegeneration. Our findings revealed that HD exposure damaged nigrostriatal dopaminergic system through αMβ2-NOX2 axis-mediated microglial activation, providing, for the first time, experimental evidence for n-hexane exposure contributing to the etiology of PD.

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“…Membrane translocation of cytosolic subunits is necessary for the activation of NADPH oxidase (Lambeth, 2004 ; Rastogi et al, 2017 ). Translocation of p47 phox to the plasma membrane may reflect the activation of NADPH oxidase activation (Hu et al, 2010 ; Wang et al, 2014 ; Hou et al, 2017b ). Previous reports have found that NADPH oxidase can be activated and produce a large amount of related ROS in the brain of a PD model and that it plays a key role in chronic neuroinflammation and related dopaminergic neurodegeneration in PD (Peterson and Flood, 2012 ; Qin et al, 2013 ; Wang et al, 2015 ; Hou et al, 2017a ).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Inhibits Activation of NADPH Oxidase/p38 MAPK Pathway and Enhances Expression of Antioxidant Protein in Parkinson Disease Models

Tong

Zhang

Meng

et al. 2018

Front. Mol. Neurosci.

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Evidence suggests that oxidative stress is involved in the pathogenesis of Parkinson disease (PD). Simvastatin has been suggested to protect against oxidative stress in several diseases. However, the molecular mechanisms by which simvastatin protects against neuropathology and oxidative damage in PD are poorly elucidated. In this study, we aimed to investigate the potential neuroprotective effects of simvastatin owing to its anti-oxidative properties in 6-hydroxydopamine (6-OHDA)-treated SH-SY5Y cells and mice. The results of 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence and CCK-8 assay demonstrated that simvastatin reduced intracellular reactive oxygen species (ROS) levels and reversed apoptosis in 6-OHDA-treated SH-SY5Y cells. Mechanistic studies revealed that 6-OHDA-induced activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/p38 mitogen-activated protein kinase (MAPK) pathway was inhibited and nuclear factor-κB (NF-κB) nuclear transcription decreased in SH-SY5Y cells after simvastatin treatment. Enhanced expression levels of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and glutamate-cysteine ligase modifier subunit (GCLM) were observed after simvastatin treatment in 6-OHDA-treated SH-SY5Y cells. In vivo studies revealed that administration of simvastatin by gavage decreased limb-use asymmetry and apomorphine-induced rotations in 6-OHDA-lesioned mice. Simvastatin increased dopaminergic neurons and reduced protein tyrosine nitration and gliosis in the midbrain of PD mice. An inhibitory effect on activation of the NADPH oxidase/p38 MAPK was observed, and increased antioxidant protein expression in the midbrain were seen in the simvastatin plus 6-OHDA group compared with the 6-OHDA-lesioned group. Taken together, these results demonstrate that simvastatin might inhibit the activation of NADPH oxidase/p38 MAPK pathway, enhance antioxidant protein expression and protect against oxidative stress, thereby providing a novel antioxidant mechanism that has therapeutic validity.

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Paraquat and maneb co-exposure induces noradrenergic locus coeruleus neurodegeneration through NADPH oxidase-mediated microglial activation

Cited by 41 publications

References 61 publications

Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization

Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization

2,5-Hexanedione induces dopaminergic neurodegeneration through integrin αMβ2/NADPH oxidase axis-mediated microglial activation

Simvastatin Inhibits Activation of NADPH Oxidase/p38 MAPK Pathway and Enhances Expression of Antioxidant Protein in Parkinson Disease Models

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