title: Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death.
abstract: BACKGROUND
  We previously found that cyclooxygenase 2 (COX-2) was expressed in dying oligodendrocytes at the onset of demyelination in the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model of multiple sclerosis (MS) (Carlson et al. J.Neuroimmunology 2006, 149:40). This suggests that COX-2 may contribute to death of oligodendrocytes.
  
  
  OBJECTIVE
  The goal of this study was to examine whether COX-2 contributes to excitotoxic death of oligodendrocytes and potentially contributes to demyelination.
  
  
  METHODS
  The potential link between COX-2 and oligodendrocyte death was approached using histopathology of MS lesions to examine whether COX-2 was expressed in dying oligodendrocytes. COX-2 inhibitors were examined for their ability to limit demyelination in the TMEV-IDD model of MS and to limit excitotoxic death of oligodendrocytes in vitro. Genetic manipulation of COX-2 expression was used to determine whether COX-2 contributes to excitotoxic death of oligodendrocytes. A transgenic mouse line was generated that overexpressed COX-2 in oligodendrocytes. Oligodendrocyte cultures derived from these transgenic mice were used to examine whether increased expression of COX-2 enhanced the vulnerability of oligodendrocytes to excitotoxic death. Oligodendrocytes derived from COX-2 knockout mice were evaluated to determine if decreased COX-2 expression promotes a greater resistance to excitotoxic death.
  
  
  RESULTS
  COX-2 was expressed in dying oligodendrocytes in MS lesions. COX-2 inhibitors limited demyelination in the TMEV-IDD model of MS and protected oligodendrocytes against excitotoxic death in vitro. COX-2 expression was increased in wild-type oligodendrocytes following treatment with Kainic acid (KA). Overexpression of COX-2 in oligodendrocytes increased the sensitivity of oligodendrocytes to KA-induced excitotoxic death eight-fold compared to wild-type. Conversely, oligodendrocytes prepared from COX-2 knockout mice showed a significant decrease in sensitivity to KA induced death.
  
  
  CONCLUSIONS
  COX-2 expression was associated with dying oligodendrocytes in MS lesions and appeared to increase excitotoxic death of oligodendrocytes in culture. An understanding of how COX-2 expression influences oligodendrocyte death leading to demyelination may have important ramifications for future treatments for MS.
authors.affiliation: Geriatric Research, Education Clinical Center (GRECC) VASLCHCS, Salt Lake City, UT, USA. noel.carlson@va.gov
authors.forename: Noel G
authors.initials: NG
authors.lastname: Carlson
authors.forename: Monica A
authors.initials: MA
authors.lastname: Rojas
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Redd
authors.forename: Philip
authors.initials: P
authors.lastname: Tang
authors.forename: Blair
authors.initials: B
authors.lastname: Wood
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hill
authors.forename: John W
authors.initials: JW
authors.lastname: Rose
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000473:pathology; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000473:pathology; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000502:physiology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009103:Multiple Sclerosis / Q000473:pathology; D009836:Oligodendroglia / Q000201:enzymology*; D009924:Organ Culture Techniques; D013116:Spinal Cord / Q000502:physiology; D017945:Theilovirus
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D018698:Glutamic Acid; D051546:Cyclooxygenase 2
references.citation: J Neuroimmunol. 1994 Oct;54(1-2):117-27
references.pmid: 7523442
references.citation: Can J Neurol Sci. 1987 Aug;14(3):255-61
references.pmid: 3311324
references.citation: Nat Neurosci. 2005 Mar;8(3):262-4
references.pmid: 15746910
references.citation: J Neural Transm Suppl. 2000;(60):375-85
references.pmid: 11205156
references.citation: J Neurosci. 2003 Oct 22;23(29):9519-28
references.pmid: 14573531
references.citation: N Engl J Med. 2000 Sep 28;343(13):938-52
references.pmid: 11006371
references.citation: Adv Immunol. 1996;62:167-215
references.pmid: 8781269
references.citation: Nat Med. 2000 Jan;6(1):62-6
references.pmid: 10613825
references.citation: Ann Neurol. 2002 Dec;52(6):771-8
references.pmid: 12447931
references.citation: Brain. 2006 Aug;129(Pt 8):1984-92
references.pmid: 16835249
references.citation: Brain Res Brain Res Rev. 2000 Apr;32(2-3):380-412
references.pmid: 10760549
references.citation: Infect Immun. 1975 May;11(5):1147-55
references.pmid: 164412
references.citation: Toxicol Sci. 2006 Jan;89(1):265-70
references.pmid: 16237196
references.citation: J Neurosci Res. 2003 Jan 1;71(1):79-88
references.pmid: 12478616
references.citation: Arch Neurol. 2006 Jul;63(7):1005-8
references.pmid: 16831971
references.citation: J Neuroophthalmol. 2006 Jun;26(2):87-94
references.pmid: 16845306
references.citation: J Neurosci. 2001 Oct 15;21(20):8198-209
references.pmid: 11588192
references.citation: J Clin Immunol. 2006 Jan;26(1):73-85
references.pmid: 16418805
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1294-9
references.pmid: 11158633
references.citation: N Engl J Med. 2004 Oct 21;351(17):1709-11
references.pmid: 15470192
references.citation: Neurobiol Dis. 2008 Mar;29(3):543-51
references.pmid: 18178094
references.citation: Pharmacol Rev. 1994 Jun;46(2):205-29
references.pmid: 7938166
references.citation: Nat Med. 2006 Feb;12(2):225-9
references.pmid: 16432513
references.citation: J Neurosci. 2004 Jan 7;24(1):257-68
references.pmid: 14715958
references.citation: J Neuroinflammation. 2007 Jul 16;4:18
references.pmid: 17634127
references.citation: J Pharmacol Exp Ther. 2000 May;293(2):417-25
references.pmid: 10773011
references.citation: Eur J Pharmacol. 2005 Jul 4;517(1-2):17-27
references.pmid: 15964567
references.citation: Trends Pharmacol Sci. 2006 Sep;27(9):458-60
references.pmid: 16870271
references.citation: N Engl J Med. 2006 Mar 2;354(9):942-55
references.pmid: 16510748
references.citation: Am J Pathol. 2001 Jun;158(6):2057-66
references.pmid: 11395383
references.citation: N Engl J Med. 2004 Oct 21;351(17):1707-9
references.pmid: 15470193
references.citation: J Neuroimmunol. 2006 May;174(1-2):21-31
references.pmid: 16516308
references.citation: J Neurotrauma. 2006 Dec;23(12):1895-903
references.pmid: 17184197
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21807-12
references.pmid: 19995978
references.citation: Mult Scler. 2004 Dec;10(6):636-42
references.pmid: 15584488
references.citation: Annu Rev Immunol. 2005;23:683-747
references.pmid: 15771584
references.citation: J Neuroinflammation. 2009 Feb 17;6:5
references.pmid: 19222857
references.citation: J Neuroimmunol. 2004 Jun;151(1-2):171-9
references.pmid: 15145615
references.citation: Trends Neurosci. 2001 Apr;24(4):224-30
references.pmid: 11250007
references.citation: J Neuropathol Exp Neurol. 1996 Jun;55(6):673-86
references.pmid: 8642393
references.citation: J Neuroimmunol. 1999 Jan 1;93(1-2):53-71
references.pmid: 10378869
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1059-64
references.pmid: 11158594
references.citation: Neurology. 2005 Apr 12;64(7):1267-9
references.pmid: 15824361
references.citation: Am J Pathol. 1999 Sep;155(3):995-1004
references.pmid: 10487857
references.citation: J Neuroimmunol. 2004 Apr;149(1-2):40-9
references.pmid: 15020063
references.citation: J Neuroimmunol. 1998 Aug 1;88(1-2):45-56
references.pmid: 9688323
references.citation: FASEB J. 2001 Oct;15(12):2057-72
references.pmid: 11641233
references.citation: J Cereb Blood Flow Metab. 1999 Nov;19(11):1213-9
references.pmid: 10566967
references.citation: J Neurosci. 1999 Jan 15;19(2):759-74
references.pmid: 9880596
references.citation: Brain Res. 2005 Dec 20;1066(1-2):71-7
references.pmid: 16360658
references.citation: Science. 2004 Dec 17;306(5704):2111-5
references.pmid: 15604411
references.citation: J Immunol. 1999 Oct 1;163(7):3963-8
references.pmid: 10490998
references.citation: Nat Med. 2000 Jan;6(1):67-70
references.pmid: 10613826
references.citation: Am J Ther. 1995 Sep;2(9):711-720
references.pmid: 11854849
references.citation: Ann Neurol. 2004 May;55(5):668-75
references.pmid: 15122707
references.citation: J Neurosci. 1997 Apr 15;17(8):2746-55
references.pmid: 9092596