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. © 2010 carlson et al; licensee biomed central ltd.