Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson's disease model

Hou, Liyan; Sun, Fuqiang; Huang, Ruixue; Sun, Wei; Zhang, Dan; Wang, Qingshan

doi:10.1016/j.redox.2019.101134

Cited by 90 publications

(72 citation statements)

References 77 publications

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“…To investigate whether rotenone-induced cognitive de cits was associated with hippocampal and cortical neuron damage, neuronal cells were immunostained with neuron-speci c anti-Neu-N antibody. As illustrated in Fig [15,26]. In agreement with neuronal loss, immunohistochemical analysis revealed a reduced density of hippocampal and cortical PSD-95 immunostaining in 1.5 mg/kg rotenone-treated mice ( Fig.…”

Section: Rotenone Dose-dependently Induces Neuronal Damagesupporting

confidence: 72%

“…PD is traditionally recognized as a movement disorder with progressive loss of nigral dopaminergic neurons [32]. However, accumulating evidence suggests that PD is a heterogeneous multisystem disorder and patients with PD display both motor de cits and multiple nonmotor symptoms [15,33]. Cognitive impairments are one of the most common nonmotor symptoms in patients with PD.…”

Section: Discussionmentioning

confidence: 99%

“…Morris water maze (MWM) test was performed as described previously [15]. A video camera was used to record the swimming paths of mice.…”

Section: Morris Water Maze Testmentioning

confidence: 99%

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Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Zhang

Hou

et al. 2020

Preprint

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BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

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Section: Rotenone Dose-dependently Induces Neuronal Damagesupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Zhang

Hou

et al. 2020

Preprint

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“…As activation of the NF-κB and STAT1 pathways plays an essential role in in ammatory responses [46][47][48], we determined if ARRBs could regulate these two pathways. siRNA-mediated ARRB1 knockdown signi cantly inhibited, whereas ARRB2 knockdown stimulated, the activation of inhibitor of NF-κB (IκB) kinase β (IKKβ) and p65 in the NF-κB pathway in BMDMs treated with LPS plus IFN-γ ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

Fang

Jiang

et al. 2020

Preprint

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Background Although β-arrestins (ARRBs) regulate diverse physiological and pathophysiological processes, their function and regulation in Parkinson’s disease (PD) remain poorly defined. Methods We measured expression of ARRB1 and ARRB2 in liposaccharide (LPS)-induced and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. ARRB1-deficient and ARRB2-deficient mouse were used to assess the impact of ARRBs on dopaminergic (DA) neuron loss and microglia activation in PD mouse models. After primary mouse DA neurons were exposed to the conditioned medium from ARRB1 knockdown or ARRB2 knockout microglia stimulated by LPS plus interferon γ (IFN-γ), the degeneration of DA neurons was quantified. Gain- and loss-of-function studies were used to study the effects of ARRBs on microglia activation in vitro. To further understand the mechanism, we measured the activation of classical inflammatory pathways and used RNA sequencing to identify the novel downstream effector of ARRBs. Result In this study, we demonstrate that expression of ARRB1 and ARRB2, particularly in microglia, is reciprocally regulated in PD mouse models. ARRB1 ablation ameliorates, whereas ARRB2 knockout aggravates, the pathological features of PD, including DA neuron loss, neuroinflammation and microglia activation in vivo, as well as microglia-mediated neuron damage and inflammation in vitro. In parallel, ARRB1 and ARRB2 produce adverse effects on the activation of inflammatory signal transducers and activators of transcription 1 (STAT1) and nuclear factor-κB (NF-κB) pathways in microglia. We also show that two ARRBs competitively interact with activated p65 in the NF-κB pathway and that nitrogen permease regulator-like 3 (Nprl3), a functionally poorly characterized protein, is a novel effector acting downstream of both ARRBs. Conclusion Collectively, these data demonstrate that two closely related ARRBs have completely opposite functions in microglia-mediated inflammatory responses, via Nprl3, and differentially affect the pathogenesis of PD, and suggest a potential therapeutic strategy.

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“…In the future, it is believed that the combined effect such as pesticides and genes, different kinds of pesticides, and pesticides and lifestyle will attract increasing attention. Till now, the combination of paraquat and maneb has been put forward and put into use many times (24,38,42,43,66,67). Thirdly, the pesticide-induced PD models are less well established, and almost all of them are rotenone-induced PD models and PD models induced by paraquat combined with maneb (45).…”

Section: Discussionmentioning

confidence: 99%

A Scientometric Analysis and Visualization of Research on Parkinson's Disease Associated With Pesticide Exposure

Liu

Zhang

et al. 2020

Front. Public Health

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The etiology and pathogenesis of Parkinson's disease (PD) have not yet been clearly described. Both genetic and environmental factors contribute to the onset and progression of PD. Some pesticides have been demonstrated to be associated with PD by many previous studies and experiments, and an increasing number of researchers have paid attention to this area in recent years. This paper aims to explore the knowledge structure, analyze the current research hot spots, and discuss the research trend through screening and summarizing the present literature. Based on 1767 articles from the Web of Science Core Collection and PubMed database, this study carried out the analysis from the keywords, cited references, countries, authors, and some other aspects by using Citespace. The hot topics, valuable articles, and productive authors in this research field could be found after that. To the best of our knowledge, this is the first study to specifically visualize the relationship between pesticide exposure and PD, and forecast research tendency in the future.

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Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson's disease model

Cited by 90 publications

References 77 publications

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

A Scientometric Analysis and Visualization of Research on Parkinson's Disease Associated With Pesticide Exposure

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