Cytotoxicity of microglia

Bánati, Richard B.; Gehrmann, Jochen; Schubert, Peter; Kreutzberg, Georg W.

doi:10.1002/glia.440070117

Cited by 974 publications

(282 citation statements)

References 68 publications

(33 reference statements)

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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

231

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: 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

231

179

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“…They are highly sensitive to changes in their microenvironment and rapidly become activated in response to pathological events [31]. Microglia in their activated state express increased levels of major histocompatibility complex type II (MHCII) and secrete a host of neurotoxic factors such as tumour necrosis factor α (TNF α), interferon γ (IFN γ ), interleukin-1β (IL-1β) and reactive oxygen intermediates [32]. These factors often work in synergy to fuel inflammatory responses which can eventually lead to neurodegeneration [33].…”

Section: Introductionmentioning

confidence: 99%

Development of Ligands for the Peripheral Benzodiazepine Receptor

James¹,

Selleri²,

Kassiou

2006

CMC

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Abstract:The peripheral benzodiazepine receptor (PBR) initially characterised as a high affinity binding site for diazepam, is densely distributed in most peripheral organs whilst only moderately expressed in the healthy brain. The predominant cell type expressing the PBR at regions of central nervous system (CNS) pathology are activated microglial cells. Under neuroinflammatory conditions there is an over-expression of PBR binding sites indicating that measurements of PBR density can act as a useful index of brain disease activity. The PBR is now considered a significant therapeutic and diagnostic target which has provided the impetus for PBR ligand development. There are several classes of PBR ligands available including benzodiazepines (Ro5 -4864), isoquinoline carboxamides (PK 11195), indoleacetamides (FGIN-1-27), phenoxyphenyl-acetamides (DAA1106) and pyrazolopyrimidines (DPA-713). Subsequent conformationally restrained isoquinoline and indoleacetamide analogues have been synthesised in an attempt to yield PBR ligands with superior affinity and brain kinetics. Even though the PBR has been linked to a number of biochemical processes, including cell proliferation, apoptosis, steroidogenesis, porphyrin transport and immunomodulation, its exact physiological role is yet to be deciphered. Selective PBR ligands with favourable in vivo binding properties and kinetics is required to gain a more complete understanding on the normal functioning of the PBR and the chemical pathways underlying several pathological conditions. Novel PBR ligands with unique binding properties and functional activity may also generate information on the localisation of the PBR and the possibility of PBR subtypes. This review highlights the main classes of PBR ligands to date. In addition the biological activity and therapeutic potential of certain PBR ligands is discussed.

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“…The close spatial relationship between the displaced microglial cells and the degenerating photoreceptor cells suggests that microglial cells might be involved in photoreceptor cell death. Activated microglia secrete cytotoxic factors such as free oxygen intermediates, proteases, and excitatory amino acids that may induce neuronal degeneration (5)(6)(7). Microglial cells also secrete tumor necrosis factor-␣ (TNF-␣) (8), interleukin-1 (9), and tumor inhibitory molecules such as gliastatin 1 (10).…”

mentioning

confidence: 99%

Microglia-derived Pronerve Growth Factor Promotes Photoreceptor Cell Death via p75 Neurotrophin Receptor

Srinivasan

Roque

Hempstead

et al. 2004

Journal of Biological Chemistry

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Reports implicating microglia-derived nerve growth factor (NGF) during programmed cell death in the developing chick retina led us to investigate its possible role in degenerative retinal disease. Freshly isolated activated retinal microglia expressed high molecular weight forms of neurotrophins including that of nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. Conditioned media from cultured retinal microglia (MGCM) consistently yielded a ϳ32-kDa NGF-reactive band when supplemented with bovine serum albumin (BSA) or protease inhibitors (PI); and promoted cell death that was suppressed by NGF immunodepletion in a mouse photoreceptor cell line (661w). The ϳ32 kDa protein was partially purified (MGCM/p32) and was highly immunoreactive with a polyclonal anti-pro-NGF antibody. Both MGCM/p32 and recombinant pro-NGF protein promoted cell death in 661w cultures. Increased levels of pro-NGF mRNA and protein were observed in the RCS rat model of retinal dystrophy. MGCM-mediated cell death was reversed by p75NTR antiserum in p75NTR ؉ /trkA ؊ 661w cells. Our study shows that a ϳ32 kDa pro-NGF protein released by activated retinal microglia promoted degeneration of cultured photoreceptor cells. Moreover, our study suggests that defective post-translational processing of NGF might be involved in photoreceptor cell loss in retinal dystrophy.

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Cytotoxicity of microglia

Cited by 974 publications

References 68 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

Development of Ligands for the Peripheral Benzodiazepine Receptor

Microglia-derived Pronerve Growth Factor Promotes Photoreceptor Cell Death via p75 Neurotrophin Receptor

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