Critical role of microglial NADPH oxidase‐derived free radicals in the in vitro MPTP model of Parkinson's disease

Gao, Hui‐Ming; Liu, Bin; Zhang, Wanqin; Hong, Jau–Shyong

doi:10.1096/fj.03-0109fje

Cited by 282 publications

(295 citation statements)

References 55 publications

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“…cMMP-3 caused dopamine cell death in mesencephalic neuron-glia mixed culture of wildtype mice but this was attenuated in the culture of NADPH oxidase (NADPHO) subunit null mice (gp91 phox-/-), suggesting that NADPHO mediated the cMMP-3-induced microglial production of superoxide and dopamine cell death (Kim et al, in press). This is critical finding to understand microgliosis in PD, as previous studies have identified that NADPHO-mediated microglial superoxide production is a mandatory microglial component to contribute MPP+ and MPTP induced dopamine toxicity both in vivo and in vitro Gao et al, 2003). Furthermore, in the MPTP-injected animal model of PD, nigrostriatal dopamine neuronal degeneration, microglial activation and superoxide generation were largely attenuated in MMP-3-/-mice.…”

Section: Matrix Metalloproteinase-3 (Mmp-3)mentioning

confidence: 82%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

573

450

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Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1β, TNF-α, IL-6), NO, PGE2, and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

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Section: Matrix Metalloproteinase-3 (Mmp-3)mentioning

confidence: 82%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

573

450

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“…The ROS inducing these molecular modifications are generated by microglial NADPH oxidase and play an important role in the development of oxidative stress in the MPTP model of PD (66). Several studies (7,67), including our recent investigations (4,5), have implicated the activation of microglial NADPH oxidase in DA neuron degeneration in SN of MPTP-treated mice. The present study further showed that MPTP induces activation of NADPH oxidase, confirmed by membrane translocation of p47 phox and Rac-1, the cytosolic components of NADPH oxidase, resulting in increased ROS and oxidative damage to nucleic acids and proteins in the SN, as assessed using hydroethidine staining, 8-OHdG immunostaining, and Western blot analysis (to ascertain the levels of protein carbonylation), respectively.…”

Section: Discussionmentioning

confidence: 96%

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Chung

Bok

Huh

et al. 2011

The Journal of Immunology

106

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This study examined whether the cannabinoid receptor type 1 (CB1) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB1 receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB1 receptor. The present in vivo and in vitro findings clearly indicate that the CB1 receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson’s disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage.

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“…NADPH oxidase appears also to be critical in mediating injury under other pathological conditions. For example, the oxidase has been implicated in nerve growth factor deprivation- (40), fibrillar amyloid ␤-(41) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in vitro (42), in death of dopaminergic neurons in an animal model of Parkinson's disease (43), and in neurotoxicity in a stroke model (44). All of the emerging evidence suggests that NADPH oxidase may play crucial roles in multiple diseases and disorders of the CNS, including neurodegenerative diseases, hypoxic͞ischemic injury, and white matter injury.…”

Section: Discussionmentioning

confidence: 99%

Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes

Lǐ

Baud

Vartanian

et al. 2005

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

323

255

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Reactive microglia in the CNS have been implicated in the pathogenesis of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, the mechanism by which activated microglia kill oligodendrocytes (OLs) remains elusive. Here we show that lipopolysaccharide (LPS)-induced death of developing OLs is caused by microglia-derived peroxynitrite, the reaction product of nitric oxide (NO) and superoxide anion. Blocking peroxynitrite formation with nitric oxide synthase inhibitors, superoxide dismutase mimics, or a decomposition catalyst abrogated the cytotoxicity. Only microglia, but not OLs, expressed inducible NO synthase (iNOS) after LPS challenge; microglia from iNOS knockout mice were not cytotoxic upon activation. The molecular source for superoxide was identified as the superoxidegenerating enzyme NADPH oxidase. The oxidase was activated upon LPS exposure, and its inhibition prevented microglial toxicity toward OLs. Furthermore, microglia isolated from mice deficient in the catalytic component of the oxidase, gp91 phox , failed to induce cell death. Our results reveal a role for NADPH oxidase in LPSinduced OL death and suggest that peroxynitrite produced by iNOS and NADPH oxidase in activated microglia may play an important role in the pathogenesis of white matter disorders.inflammation ͉ lipopolysaccharide ͉ cerebral palsy ͉ reactive nitrogen species ͉ periventricular leukomalacia M icroglia are the resident macrophage-like cells of the CNS.They play a pivotal role in the innate immune response of CNS and are the first line of defense against microorganism invasion and injury (1). Localized activation of microglia, however, has also been implicated in the pathogenesis of a number of neurological diseases and disorders, including ischemia; AIDS-associated dementia (2); chronic neurodegenerative diseases (3), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and white matter disorders, such as multiple sclerosis (4) and periventricular leukomalacia (PVL) (5). Microglia are extremely responsive to environmental or immunological challenges and are the predominant cell type producing inflammation-mediated neurodegeneration. Upon activation, microglia release proinflammatory molecules, such as cytokines and chemokines, and mediators of cell injury, such as proteases and reactive oxygen species (ROS)͞reactive nitrogen species (6-8). Although necessary for normal functions, activation of microglia requires tight regulation to avoid bystander injury to other CNS cells. The identification of primary toxic factors, localization of their molecular sources, and the elucidation of signaling pathways associated with microglial overactivation are therefore of paramount importance to our understanding of cellular injury in the CNS.PVL is the lesion of cerebral white matter that underlies most cases of cerebral palsy developing in premature infants (9). It is characterized by focal necrotic lesions in the deep white matter and by diffuse injury to premyelinatin...

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Critical role of microglial NADPH oxidase‐derived free radicals in the in vitro MPTP model of Parkinson's disease

Cited by 282 publications

References 55 publications

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes

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