title: LPS and TNF alpha modulate AMPA/NMDA receptor subunit expression and induce PGE2 and glutamate release in preterm fetal ovine mixed glial cultures.
abstract: BACKGROUND
  White matter injury (WMI) is the major antecedent of cerebral palsy in premature infants, and is often associated with maternal infection and the fetal inflammatory response. The current study explores the therapeutic potential of glutamate receptor blockade or cyclooxygenase-2 (COX-2) inhibition for inflammatory WMI.
  
  
  METHODS
  Using fetal ovine derived mixed glia cultures exposed to tumour necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl D-aspartate (NMDA) glutamate receptors and their contribution to inflammation mediated pre-oligodendrocyte (OL) death was evaluated. The functional significance of TNF-α and COX-2 signalling in glutamate release in association with TNF-α and LPS exposure was also assessed.
  
  
  RESULTS
  AMPA and NMDA receptors were expressed in primary mixed glial cultures on developing OLs, the main cell-type present in fetal white matter at a period of high risk for WMI. We show that glutamate receptor expression and configuration are regulated by TNF-α and LPS exposure, but AMPA and NMDA blockade, either alone or in combination, did not reduce pre-OL death. Furthermore, we demonstrate that glutamate and prostaglandin E2 (PGE2) release following TNF-α or LPS are mediated by a TNF-α-COX-2 dependent mechanism.
  
  
  CONCLUSIONS
  Overall, these findings suggest that glial-localised glutamate receptors likely play a limited role in OL demise associated with chronic inflammation, but supports the COX-2 pathway as a potential therapeutic target for infection/inflammatory-mediated WMI.
authors.forename: Luke
authors.initials: L
authors.lastname: Weaver-Mikaere
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
authors.forename: Murray D
authors.initials: MD
authors.lastname: Mitchell
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.affiliation: The Liggins Institute, The University of Auckland, 85 Park Rd, Grafton, Private Bag 92019, Auckland 1142, New Zealand. m.fraser@auckland.ac.nz.
authors.forename: Mhoyra
authors.initials: M
authors.lastname: Fraser
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism; D005333:Fetus; D018698:Glutamic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity; D009457:Neuroglia / Q000378:metabolism*; D011863:Radioimmunoassay; D060888:Real-Time Polymerase Chain Reaction; D018091:Receptors, AMPA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: D008070:Lipopolysaccharides; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D051546:Cyclooxygenase 2; D015232:Dinoprostone