Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury

Kimberly R. Byrnes, David J. Loane, Bogdan A. Stoica, Jiangyang Zhang, Alan I. Faden

Research output: Contribution to journalArticle

Abstract

Background: Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors in vitro, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.Methods: One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.Results: Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.Conclusion: Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.

Original languageEnglish (US)
Article number43
JournalJournal of Neuroinflammation
Volume9
DOIs
StatePublished - Feb 28 2012

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Metabotropic Glutamate 5 Receptor
Microglia
NADP
Oxidoreductases
Biochemical Phenomena
Excitatory Amino Acid Antagonists
Metabotropic Glutamate Receptors
Diffusion Tensor Imaging
Traumatic Brain Injury
Hippocampus
Magnetic Resonance Imaging
Wounds and Injuries

Keywords

  • Delayed treatment
  • Metabotropic glutamate receptor 5
  • Microglia
  • Neuroprotection
  • Traumatic brain injury

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury. / Byrnes, Kimberly R.; Loane, David J.; Stoica, Bogdan A.; Zhang, Jiangyang; Faden, Alan I.

In: Journal of Neuroinflammation, Vol. 9, 43, 28.02.2012.

Research output: Contribution to journalArticle

Byrnes, Kimberly R. ; Loane, David J. ; Stoica, Bogdan A. ; Zhang, Jiangyang ; Faden, Alan I. / Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury. In: Journal of Neuroinflammation. 2012 ; Vol. 9.
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abstract = "Background: Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors in vitro, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.Methods: One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.Results: Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.Conclusion: Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.",
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AU - Loane, David J.

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