title: The role of the prostaglandin E2 receptors in vulnerability of oligodendrocyte precursor cells to death.
abstract: BACKGROUND
  Activity of cyclooxygenase 2 (COX-2) in mouse oligodendrocyte precursor cells (OPCs) modulates vulnerability to excitotoxic challenge. The mechanism by which COX-2 renders OPCs more sensitive to excitotoxicity is not known. In the present study, we examined the hypothesis that OPC excitotoxic death is augmented by COX-2-generated prostaglandin E2 (PGE2) acting on specific prostanoid receptors which could contribute to OPC death.
  
  
  METHODS
  Dispersed OPC cultures prepared from mice brains were examined for expression of PGE2 receptors and the ability to generate PGE2 following activation of glutamate receptors with kainic acid (KA). OPC death in cultures was induced by either KA, 3'-O-(Benzoyl) benzoyl ATP (BzATP) (which stimulates the purinergic receptor P2X7), or TNFα, and the effects of EP3 receptor agonists and antagonists on OPC viability were examined.
  
  
  RESULTS
  Stimulation of OPC cultures with KA resulted in nearly a twofold increase in PGE2. OPCs expressed all four PGE receptors (EP1-EP4) as indicated by immunofluorescence and Western blot analyses; however, EP3 was the most abundantly expressed. The EP3 receptor was identified as a candidate contributing to OPC excitotoxic death based on pharmacological evidence. Treatment of OPCs with an EP1/EP3 agonist 17 phenyl-trinor PGE2 reversed protection from a COX-2 inhibitor while inhibition of EP3 receptor protected OPCs from excitotoxicity. Inhibition with an EP1 antagonist had no effect on OPC excitotoxic death. Moreover, inhibition of EP3 was protective against toxic stimulation with KA, BzATP, or TNFα.
  
  
  CONCLUSIONS
  Therefore, inhibitors of the EP3 receptor appear to enhance survival of OPCs following toxic challenge and may help facilitate remyelination.
authors.affiliation: Geriatric Research, Education Clinical Center (GRECC), Salt Lake City, USA. noel.carlson@neuro.utah.edu.|Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. noel.carlson@neuro.utah.edu.|Center on Aging, University of Utah, Salt Lake City, UT, USA. noel.carlson@neuro.utah.edu.|Brain Institute, University of Utah, Salt Lake City, UT, USA. noel.carlson@neuro.utah.edu.|Departments of Neurobiology & Anatomy, University of Utah, Salt Lake City, UT, USA. noel.carlson@neuro.utah.edu.|Neuroimmunology and Neurovirology Division, Department of Neurology, University of Utah, Salt Lake City, UT, USA. noel.carlson@neuro.utah.edu.|Neurovirology Research Laboratory, (151B), VA SLCHCS, 500 Foothill Dr., Salt Lake City, UT, 84148, USA. noel.carlson@neuro.utah.edu.
authors.forename: Noel G
authors.initials: NG
authors.lastname: Carlson
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. satya.bellamkonda@utah.edu.
authors.forename: Satya
authors.initials: S
authors.lastname: Bellamkonda
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. Linda.schmidt@hsc.utah.edu.
authors.forename: Linda
authors.initials: L
authors.lastname: Schmidt
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. jwredd@gmail.com.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Redd
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. tom.huecksteadt@hsc.utah.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Huecksteadt
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. L.Marissa.Weber@utah.edu.
authors.forename: Lauren Marissa
authors.initials: LM
authors.lastname: Weber
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. edavis0519@hotmail.com.
authors.forename: Ethan
authors.initials: E
authors.lastname: Davis
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. blair.wood@hsc.utah.edu.
authors.forename: Blair
authors.initials: B
authors.lastname: Wood
authors.affiliation: Ono Pharmaceutical Co., Osaka, Japan. t.maruyama@ono.co.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Neurovirology Laboratory, VASLCHCS, Salt Lake City, UT, USA. jrose@genetics.utah.edu.|Brain Institute, University of Utah, Salt Lake City, UT, USA. jrose@genetics.utah.edu.|Neuroimmunology and Neurovirology Division, Department of Neurology, University of Utah, Salt Lake City, UT, USA. jrose@genetics.utah.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Rose
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors
chemical_list: C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D017470:Receptors, Glutamate; D017452:Receptors, IgG; D018078:Receptors, Prostaglandin E; D013450:Sulfones; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007608:Kainic Acid