The role of glial cells in Parkinsonʼs disease

Vila, Miquel; Jackson‐Lewis, Vernice; Guégan, Christelle; Wu, Du Chu; Teismann, Peter; Choi, Dong‐Kug; Tieu, Kim; Przedborski, Serge

doi:10.1097/00019052-200108000-00009

Cited by 305 publications

(200 citation statements)

References 49 publications

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“…4G). Activation of microglia has been proposed to play a pathological role in a variety of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, multiple sclerosis, AIDS dementia complex and amyotrophic lateral sclerosis (Raine, 1994;Vila et al, 2001;Minagar et al, 2002;Williams and Hickey, 2002). Activated microglia secrete many types of molecules, some classed as neuroprotective, others as neurotoxic (Zietlow et al, 1999;Kim et al, 2000;Ryu et al, 2002a).…”

Section: Discussionmentioning

confidence: 99%

Microglia expressing interleukin‐13 undergo cell death and contribute to neuronal survival in vivo

Shin

Lee

Park

et al. 2004

Glia

113

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How to minimize brain inflammation is pathophysiologically important, since inflammation induced by microglial activation can exacerbate brain damage. In the present report, we show that injection of lipopolysaccharide (LPS) into the rat cortex led to increased levels of interleukin-13 (IL-13) and to IL-13 immunoreactivity, followed by the substantial loss of microglia at 3 days post-LPS. IL-13 levels in LPS-injected cortex reached a peak at 12 h post-injection, remained elevated at 24 h, and returned to basal levels at day 4. In parallel, IL-13 immunoreactivity was detected as early as 12 h post-LPS and maintained up to 24 h; it disappeared at 4 days. Surprisingly, IL-13 immunoreactivity was detected exclusively in microglia, but not in neurons or astrocytes. Following treatment with LPS in vitro, IL-13 expression was also induced in microglia in the presence of neurons, but not in the presence of astrocytes or in cultured pure microglia alone. In experiments designed to determine the involvement of IL-13 in microglia cell death, IL-13-neutralizing antibodies significantly increased survival of activated microglia at 3 days post-LPS. Consistent with these results, the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-␣ (TNF-␣) was sustained in activated microglia and neuronal cell death was consequently increased. Taken together, the present study is the first to demonstrate the endogenous expression of IL-13 in LPS-activated microglia in vivo, and to demonstrate that neurons may be required for IL-13 expression in microglia. Our data strongly suggest that IL-13 may control brain inflammation by inducing the death of activated microglia in vivo, resulting in an enhancement of neuronal survival.

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Section: Discussionmentioning

confidence: 99%

Microglia expressing interleukin‐13 undergo cell death and contribute to neuronal survival in vivo

Shin

Lee

Park

et al. 2004

Glia

113

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“…The presence of oxidative stress and inflammatory activity is one of the significant features of PD (Hirsch et al 1998). Since microglia are a principal source of a variety of cytotoxic compounds, including reactive oxygen species, reactive nitrogen species, pro-inflammatory cytokines, and prostaglandins (Banati et al 1993); microglial activation is known to play a key role in the pathogenesis of human PD and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model (Vila et al 2001). Several molecules released from stressed dopaminergic neurons, such as a-synuclein, neuromelanin, and matrix metalloproteinase-3 (MMP-3), are found to be involved in microglial activation (Kim et al 2005, Kim & Joh 2006.…”

Section: Introductionmentioning

confidence: 99%

Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease

Kim

Moon²,

Park

2009

Journal of Endocrinology

225

179

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Exendin-4 is a naturally occurring more potent and stable analog of glucagon-like peptide-1 (GLP-1) that selectively binds at the GLP-1 receptor. It has been recently demonstrated that GLP-1 receptor stimulation preserves dopaminergic neurons in cellular and rodent models of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity in rodents; previous studies suggest that activated microglia actively participate in the pathogenesis of PD neurodegeneration. However, the role of microglia in the neuroprotective properties of exendin-4 is still unknown. Here, we show that, in the mouse MPTP PD model, systemic administration of exendin-4 significantly attenuates the loss of substantia nigra pars compacta (SNpc) neurons and the striatal dopaminergic fibers. Exendin-4 prevents MPTP-induced microglial activation in the SNpc and striatum, and the expression of matrix metalloproteinase-3. In addition, exendin-4 also suppressed MPTP-induced expression of pro-inflammatory molecules and tumor necrosis factor a and interleukin-1b. Our data indicate that exendin-4 may act as a survival factor for dopaminergic neurons by functioning as a microgliadeactivating factor and suggest that exendin-4 may be a valuable therapeutic agent for neurodegenerative diseases such as PD.

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“…However, inflammation often damages surrounding tissues. Several studies show that brain inflammation aggravates ischemic and traumatic brain injury (Giulian and Vaca, 1993;Holmin et al, 1995), and is involved in progression of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (Gonzalez-Scarano and Baltuch, 1999;Vila et al, 2001). Therefore, control of the duration and extent of brain inflammation is an emerging therapeutic target to treat and/or prevent both acute and chronic brain diseases (Feuerstein et al, 1997;Hoozemans et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti-inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase-1 (HO-1). The H 2 O 2 -induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3-6 h, compared with that in untreated cells. Adenosine induced HO-1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3-kinase (PI3K) and Akt pathways appear to mediate HO-1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO-1 promoter activity in an ARE-dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine-induced HO-1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO-1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production. V

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The role of glial cells in Parkinsonʼs disease

Cited by 305 publications

References 49 publications

Microglia expressing interleukin‐13 undergo cell death and contribute to neuronal survival in vivo

Microglia expressing interleukin‐13 undergo cell death and contribute to neuronal survival in vivo

Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

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