Activation of group II metabotropic glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up‐regulated in Alzheimer's disease

Taylor, Dave; Diemel, Lara T.; Cuzner, M. L.; Pocock, Jennifer M.

doi:10.1046/j.1471-4159.2002.01062.x

Cited by 132 publications

(148 citation statements)

References 60 publications

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Section: Glutamate Receptorsmentioning

confidence: 99%

“…100 -104 They also express all three groups of metabotropic receptors: group I (mGluR5), 105 group II (mGluR2 and 3), 106,107 and group III (mGluR4, 6, and 8). 106,108 Stimulation with either glutamate or with ionotropic glutamate receptor agonists induces microglial proliferation, morphological changes characteristic of microglial activation, and release of IL-1␤, TNF␣, NO, and ATP. 100,101,104,109 Conversely, activation of most mGluR types inhibits microglial inflammatory responses, 107,110 -112 with the exception that mGluR2 activation promotes microglial neurotoxicity.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

“…100,101,104,109 Conversely, activation of most mGluR types inhibits microglial inflammatory responses, 107,110 -112 with the exception that mGluR2 activation promotes microglial neurotoxicity. 106,107 Microglia expression of glutamate receptor subtypes in vivo has not been extensively characterized, but protein expression of mGluR1, mGLuR2/3, and mGluR8 has been reported in microglia surrounding human multiple sclerosis lesions, 113 and expression of ionotropic glutamate receptors has been detected in reactive microglia in damaged areas of the hippocampus following ischemia. 114 The acute administration of an mGluR5 agonist after experimental stroke or spinal cord injury is neuroprotective, 115,116 and an mGluR5 agonist was also shown to reduce microglial activation in the spinal cord injury study, 116 suggesting that the neuroprotective effect of these agents may be attributable to the suppression of microglial activation.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

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Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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Section: Glutamate Receptorsmentioning

confidence: 99%

Section: Glutamate Receptorsmentioning

confidence: 99%

Section: Glutamate Receptorsmentioning

confidence: 99%

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Microglial Activation in Stroke: Therapeutic Targets

2010

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“…Activation of microglia with chromogranin A (CGA), a secretory peptide with enhanced expression in Alzheimer's disease (Munoz et al, 1990;Munoz, 1991;Yasuhara et al, 1994), leads to a reactive neurotoxic microglial phenotype (Ciesielski-Treska et al, 1998) and causes microglial glutamate release (Kingham et al, 1999). This glutamate release is involved in an autologous feedback loop to damage the microglia (Kingham et al, 1999) and to trigger neurotoxin release by activation of group II metabotropic glutamate (mGlu) receptors on these cells (Taylor et al, 2002). Exposure of microglia to amyloid ␤ peptide 25-35 (A␤25-35) also displays an underlying activation of group II mGlu receptors (Taylor et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…This glutamate release is involved in an autologous feedback loop to damage the microglia (Kingham et al, 1999) and to trigger neurotoxin release by activation of group II metabotropic glutamate (mGlu) receptors on these cells (Taylor et al, 2002). Exposure of microglia to amyloid ␤ peptide 25-35 (A␤25-35) also displays an underlying activation of group II mGlu receptors (Taylor et al, 2002). Furthermore, the direct stimulation of these receptors on microglia by specific agonists is also neurotoxic (Taylor et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Activation of Microglial Group III Metabotropic Glutamate Receptors Protects Neurons against Microglial Neurotoxicity

Taylor¹,

Diemel

Pocock³

2003

J. Neurosci.

194

168

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A reduction in microglial activation and subsequent neurotoxicity may prove critical for neuroprotection in neurodegenerative diseases. We examined the expression and functionality of group III metabotropic glutamate (mGlu) receptors on microglia. Rat microglia express mRNA and receptor protein for group III mGlu receptors mGlu4, mGlu6, and mGlu8 but not mGlu7. Activation of these receptors on microglia with the specific group III agonists (L)-2-amino-4-phosphono-butyric acid (L-AP-4) or (R,S)-phosphonophenylglycine (RS-PPG) inhibited forskolin-induced cAMP production, linking these receptors to the negative inhibition of adenylate cyclase. These agonists did not induce a fall in mitochondrial membrane potential or apoptosis in the microglia, suggesting that activation of these receptors is not in itself toxic to microglia. Fluorescence-activated cell sorting analysis revealed that activation of group III mGlu receptors induces a mild activation of the microglia, as evidence by their enhanced staining with ED1. However, this activation is not neurotoxic. Agonists of group III mGlu receptors reduced microglial reactivity when they were activated with lipopolysaccharide (LPS), chromogranin A (CGA) or amyloid ␤ peptide 25-35 (A␤25-35). Furthermore, L-AP-4 or RS-PPG treatment of microglia reduced their neurotoxicity after microglial stimulation with LPS or CGA but not A␤25-35. Similar results were obtained with microglial conditioned medium or in coculture, suggesting that the activation of microglial group III mGlu receptors may modulate the production of stable neurotoxins from the microglia. These results suggest that selective modulation of microglial group III mGlu receptors may provide a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease.

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Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents

Byrnes

Stoica

Riccio

et al. 2009

Annals of Neurology

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Objective Activation of metabotropic glutamate receptor 5 (mGluR5) has neuroprotective properties in vitro and has been reported to limit postischemic lesion volume in vivo. Previously, mGluR5 has been identified on microglia in vitro, but the effects of mGluR5 activation on inflammation in vivo or on recovery after spinal cord injury is unknown. Methods Rats received intrathecal infusion of the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) for 7 days after moderate impact spinal cord injury at T9. Complementary studies examined CHPG effects on activated spinal microglia cultures. Results Functional motor recovery was significantly increased by CHPG treatment up to 28 days after injury, with improvements in weight bearing, step taking, and coordination of stepping behavior. CHPG treatment significantly reduced lesion volume and increased white matter sparing at 28 days after injury. Administration of CHPG attenuated microglial-associated inflammatory responses in a dose-dependent fashion, including expression of ED1, Iba-1, Galectin-3, NADPH oxidase components, tumor necrosis factor-α, and inducible nitric oxide synthase. Because mGluR5 is expressed by microglial cells in the rat spinal cord, such effects may be mediated by direct action on microglial cells. mGluR5 stimulation also reduced microglial activation and decreased microglial-induced neurotoxicity in spinal cord microglia cultures; the latter effects were blocked by the selective mGluR5 antagonist MTEP. Interpretation These data demonstrate that mGluR5 activation can reduce microglial-associated inflammation, suggesting that the protective effects of mGluR5 agonists may reflect this action.

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Activation of group II metabotropic glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up‐regulated in Alzheimer's disease

Cited by 132 publications

References 60 publications

Microglial Activation in Stroke: Therapeutic Targets

Microglial Activation in Stroke: Therapeutic Targets

Activation of Microglial Group III Metabotropic Glutamate Receptors Protects Neurons against Microglial Neurotoxicity

Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents

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