title: Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Byrnes
authors.forename: David J
authors.initials: DJ
authors.lastname: Loane
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Zhang
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D053331:Ectodysplasins / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006624:Hippocampus / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009069:Movement Disorders / Q000209:etiology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D010648:Phenylacetates / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D011971:Receptors, Immunologic / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects; D018709:Statistics, Nonparametric; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: C107349:2-chloro-5-hydroxyphenylglycine; C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D053331:Ectodysplasins; C506019:Eda protein, mouse; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D008840:Microfilament Proteins; D010648:Phenylacetates; C105949:Pirb protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D011971:Receptors, Immunologic; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D005998:Glycine