Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates Microglia

Kim, Yoon Seong; Kim, Sung Soo; Cho, Jeong Je; Choi, Dong Hee; Hwang, Onyou; Shin, Dong Hoon; Chun, Hong Sung; Beal, M. Flint; Joh, Tong H.

doi:10.1523/jneurosci.4346-04.2005

Cited by 242 publications

(221 citation statements)

References 61 publications

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“…It has been reported that MMP-3 plays critical roles in dopaminergic neurodegeneration in experimental models of PD both intracellularly, by mediating apoptosis of dopaminergic neurons, and extracellularly by triggering neuroinflammation (Kim et al 2005, Choi et al 2008. Specifically, active form of MMP-3 is released from dopaminergic neuronal cells that are under cellular stress and undergoing apoptosis and leads to microglial activation and production of pro-inflammatory and neurotoxic molecules in microglia and further enhances dopaminergic cell death (Kim et al 2005(Kim et al , 2007.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, active form of MMP-3 is released from dopaminergic neuronal cells that are under cellular stress and undergoing apoptosis and leads to microglial activation and production of pro-inflammatory and neurotoxic molecules in microglia and further enhances dopaminergic cell death (Kim et al 2005(Kim et al , 2007. Furthermore, nigrostriatal dopaminergic neurodegeneration, microglial activation, and superoxide generation were substantially attenuated in MMP-3 K/K mice exposed to MPTP (Kim et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…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. Among these microglial activators, MMP-3 is known to be responsible for the activation of microglia and the release of NADPH oxidase-derived superoxide and nuclear factor-kB-mediated pro-inflammatory cytokines, and eventually exacerbates dopaminergic neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…It has been previously reported that Mmp3 is up-regulated in the hippocampus of KA-treated mice (Penkowa et al 2005), and Mmp3 is known to play an important role in dopaminergic neuronal cell death and neuroinflammation (Kim et al 2005. Therefore, we performed immunohistochemistry and RT-PCR to investigate the effect of ghrelin on KA-induced Mmp3 expression in the hippocampus.…”

Section: Ghrelin Attenuates Ka-induced Mmp3 Expressionmentioning

confidence: 97%

Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus

Lee¹,

Lim²,

Kim³

et al. 2010

Journal of Endocrinology

105

111

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Ghrelin is an endogenous ligand for GH secretagogue receptor type 1a (GHSR1a), and is produced and released mainly from the stomach. It has been recently demonstrated that ghrelin can function as a neuroprotective factor by inhibiting apoptotic pathways. Kainic acid (KA), an excitatory amino acid L-glutamate analog, causes neuronal death in the hippocampus; previous studies suggest that activated microglia and astrocytes actively participate in the pathogenesis of KA-induced hippocampal neurodegeneration. However, it is unclear whether ghrelin has neuroprotective effect in KA-induced hippocampal neurodegeneration. I.p. injection of KA produced typical neuronal cell death in the CA1 and CA3 pyramidal layers of the hippocampus, and the systemic administration of ghrelin significantly attenuated KA-induced neuronal cell death in these regions through the activation of GHSR1a. Ghrelin prevents KA-induced activation of microglia and astrocytes, and the expression of proinflammatory mediators tumor necrosis factor a, interleukin-1b, and cyclooxygenase-2. The inhibitory effect of ghrelin on the activation of microglia and astrocytes appears to be associated with the inhibition of matrix metalloproteinase-3 expression in damaged hippocampal neurons. Our data suggest that ghrelin has a therapeutic potential for suppressing KA-induced pathogenesis in the brain.

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“…Some of them are from neurons and others are from pathogens, immune cells or microglia (abd-el-Basset and Fedoroff, 1995;Tsirka, 1997;Suzumura et al, 1998;Tan et al, 1999a;Aloisi et al, 1999b;Moller et al, 2000;Kim et al, 2005). LPS, an endotoxin from the gram-negative bacterial cell wall, is a potent immunostimulant (abdel-Basset and Fedoroff, 1995).…”

Section: Molecules Involved In Microglial Activation and Signal Transmentioning

confidence: 99%

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

Kim

Joh²

2006

Exp Mol Med

581

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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Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates Microglia

Cited by 242 publications

References 61 publications

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

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

Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus

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

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