Role of cytokines in inflammatory process in Parkinson’s disease

Sawada, Makoto; Imamura, Kazuhiro; Nagatsu, Toshiharu

doi:10.1007/978-3-211-45295-0_57

Cited by 286 publications

(210 citation statements)

References 14 publications

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“…Both mitochondrial and extra-mitochondrial ROS have been shown to contribute to the degenerative process in cell cultures and animal models of PD. Several studies have shown plasma membrane NADPH oxidase is the primary enzyme responsible for generating extramitochondrial or cytosolic ROS (Serrano et al, 2003;Geiszt, 2006;Infanger et al, 2006;Sawada et al, 2006;Ushio-Fukai, 2006). NADPH oxidase and its protein subunits are mainly present in astrocytes and microglial cells (Serrano et al, 2003;Infanger et al, 2006;Takeya and Sumimoto, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, inflammation has also been suggested to contribute to the pathogenesis of PD (Beal, 2003;Hald and Lotharius, 2005;Sawada et al, 2006;Wersinger and Sidhu, 2006). ROS are among the inflammatory mediators capable of promoting neurodegeneration, which are derived from activation of microglial NADPH oxidase (Serrano et al, 2003;Infanger et al, 2006;Sawada et al, 2006;Ushio-Fukai, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…ROS are among the inflammatory mediators capable of promoting neurodegeneration, which are derived from activation of microglial NADPH oxidase (Serrano et al, 2003;Infanger et al, 2006;Sawada et al, 2006;Ushio-Fukai, 2006). NADPH oxidase is a multisubunit enzyme that catalyzes the reduction of molecular oxygen to form superoxide radicals, and is composed of gp91 phox , p22 phox , p47 phox , p67 phox , and p40 phox subunits.…”

Section: Introductionmentioning

confidence: 99%

“…NADPH oxidase is a multisubunit enzyme that catalyzes the reduction of molecular oxygen to form superoxide radicals, and is composed of gp91 phox , p22 phox , p47 phox , p67 phox , and p40 phox subunits. Under basal conditions, the p47 phox , p67 phox , and p40 phox subunits are present in the cystosol as a complex, and are separated from the transmembrane gp91 phox and p22 phox subunits (Serrano et al, 2003;Infanger et al, 2006;Sawada et al, 2006;Ushio-Fukai, 2006). Upon activation, the p47 phox subunit gets phosphorylated, and translocates to the membrane as a complex to assemble with gp91 phox and p22 phox to form an active NADPH oxidase capable of reducing oxygen to a superoxide radical(O 2 -) to generate microglial and/or extra-mitochondrial-derived ROS (Serrano et al, 2003;Infanger et al, 2006;Sawada et al, 2006;Ushio-Fukai, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Under basal conditions, the p47 phox , p67 phox , and p40 phox subunits are present in the cystosol as a complex, and are separated from the transmembrane gp91 phox and p22 phox subunits (Serrano et al, 2003;Infanger et al, 2006;Sawada et al, 2006;Ushio-Fukai, 2006). Upon activation, the p47 phox subunit gets phosphorylated, and translocates to the membrane as a complex to assemble with gp91 phox and p22 phox to form an active NADPH oxidase capable of reducing oxygen to a superoxide radical(O 2 -) to generate microglial and/or extra-mitochondrial-derived ROS (Serrano et al, 2003;Infanger et al, 2006;Sawada et al, 2006;Ushio-Fukai, 2006). NADPH oxidase is ubiquitously expressed in a wide variety of cells and organ systems, including brain regions such as hippocampus, cortex, striatum, thalamus, and amygdala (Serrano et al, 2003;Geiszt, 2006;Infanger et al, 2006;Takeya and Sumimoto, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

et al. 2007

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Oxidative stress is widely recognized as a key mediator of degenerative processes in Parkinson's disease (PD). Recently, we demonstrated that the dopaminergic toxin MPP + initiates oxidative stress to cause caspase-3-dependent apoptotic cell death in mesencephalic dopaminergic neuronal (N27) cells. In this study, we determined the source of reactive oxygen species (ROS) produced during MPP + -induced apoptotic cell death. In addition to mitochondria, plasma membrane NADPH oxidase is considered a major producer of ROS inside the cell. Here, we show that N27 cells express key NADPH oxidase subunits gp91 phox and p67 phox . We used structurally diverse NADPH oxidase inhibitors, aminoethyl-benzenesulfonylfluoride (AEBSF, 100-1000 μM), apocynin (100-1000 μM), and diphenylene iodonium (DPI, 3-30 μM), to inhibit intrinsic NADPH oxidase activity in N27 cells. Flow cytometric analysis using the ROS-sensitive dye hydroethidine revealed that AEBSF blocked 300 μM MPP + -induced ROS production for over 45 min in N27 cells, in a dose-dependent manner. Further treatment with DPI, apocynin, and SOD also blocked MPP + -induced ROS production. In Sytox cell death assays, co-treatment with AEBSF, apocynin, or DPI for 24 hr significantly suppressed MPP + -induced cytotoxic cell death. Similarly, co-treatment with these inhibitors also significantly attenuated MPP + -induced increases in caspase-3 enzymatic activity. Furthermore, quantitative DNA fragmentation ELISA assays revealed that AEBSF, DPI, and apocynin rescue N27 cells from MPP + -induced apoptotic cell death. Together, these results indicate for the first time that intracellular ROS generated by NAPDH oxidase are present within the mesencephalic neuronal cells, and are a key determinant of MPP + -mediated dopaminergic degeneration in in vitro models of dopaminergic degeneration. This study supports a critical role of NADPH oxidase in the oxidative damage in PD; targeting this enzyme may lead to novel therapies for PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

et al. 2007

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NADPH Oxidases: Structure and Function

Quinn¹

2013

Molecular Basis of Oxidative Stress

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Heat‐killed Lactobacillus murinus confers neuroprotection against dopamine neuronal loss by targeting NLRP3 inflammasome

Fan

Sheng

et al. 2022

Bioengineering & Transla Med

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The intestinal flora has become very active in studies related to Parkinson's disease (PD) in recent years. The microbe-gut-brain axis is closely related to the maintenance of brain homeostasis as well as PD pathogenesis. Alterations in gut bacteria can contribute to neuroinflammation and dopamine (DA) neurodegeneration. Lactobacillus murinus, a gram-positive bacterium, is a commensal gut bacteria present in the mammalian gut and considered as a potential probiotic due to its beneficial effects, including anti-inflammatory and antibacterial actions. In this study, the effects of live L. murinus and heat-killed L. murinus on DA neuronal damage in rats and the underlying mechanisms were investigated. Data showed that heatkilled L. murinus ameliorated 6-hydroxydopamine-induced motor dysfunctions and loss of substantia nigra DA neurons, while no protection was shown in live L. murinus treatment. At the same time, heat-killed L. murinus reduced the activation of NLRP3 inflammasome in microglia and the secretion of proinflammatory factors, thus inhibiting the development of neuroinflammation. Furthermore, heat-killed L. murinus failed to display its original neuroprotective properties in NLRP3 inflammasome knockout mice. Together, heat-killed L. murinus conferred neuroprotection against DA neuronal loss via the inhibition of microglial NLRP3 inflammasome activation. These findings provide a promising potential for future applications of L. murinus, and also beneficial strategy for PD treatment.

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Role of cytokines in inflammatory process in Parkinson’s disease

Cited by 286 publications

References 14 publications

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

NADPH Oxidases: Structure and Function

Heat‐killed Lactobacillus murinus confers neuroprotection against dopamine neuronal loss by targeting NLRP3 inflammasome

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