Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death.
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.
Carlson
Noel G
NG
Geriatric Research, Education Clinical Center (GRECC) VASLCHCS, Salt Lake City, UT, USA. noel.carlson@va.gov
Rojas
Monica A
MA
Redd
Jonathan W
JW
Tang
Philip
P
Wood
Blair
B
Hill
Kenneth E
KE
Rose
John W
JW
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
D052246:Cyclooxygenase 2 Inhibitors; D018698:Glutamic Acid; D051546:Cyclooxygenase 2
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