Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death

Abstract

BackgroundWe 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.ObjectiveThe goal of this study was to examine whether COX-2 contributes to excitotoxic death of oligodendrocytes and potentially contributes to demyelination.MethodsThe 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.ResultsCOX-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.ConclusionsCOX-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.

Pathogenesis and Progression of Multiple Sclerosis: The Role of Arachidonic Acid–Mediated Neuroinflammation

“…Specifically, COX-2 was expressed in oligodendrocytes undergoing apoptosis as indicated by immunohistochemistry experiments that found colocalization of the COX-2 protein and the apoptotic mediator caspase-3. These data were confirmed in a further study published in 2010 (16). The latter also showed that COX-2 mediates mechanisms of excitotoxicity against cultured oligodendrocytes (16).…”

“…These data were confirmed in a further study published in 2010 (16). The latter also showed that COX-2 mediates mechanisms of excitotoxicity against cultured oligodendrocytes (16). COX-2 and PGE 2 gene expression were also found in primary cultures of astrocytes from TMEV-infected mice (32).…”

“…In the TMEV model, the COX-2 selective inhibitor CAY10542, reduced demyelination by 25%, and prevented the death of oligodendrocytes (16). The efficacy of COX-2 targeting has been confirmed in the cuprizone model as well, as celecoxib greatly reduced demyelination (about 30% reduction in the corpus callosum and complete recovery in the cortex) along with a full recovery of motor abilities (35).…”

“…COX-1 is constitutively expressed, whereas COX-2 is induced during inflammation and seems to be the major source of PGE 2 production. Particularly, COX-2 expression appears to be induced in oligodendrocytes and immune cells during the processes of demyelination (15)(16)(17). The proinflammatory PGs and LTs that are upregulated in multiple sclerosis represent promising therapeutic targets as suggested by animal models of multiple sclerosis.…”

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

“…In experimental multiple sclerosis models, oligodendrocytes in apoptosis also express increased levels of COX-2 at the demyelination beginning, which seem to make these cells more susceptible to death by glutamate-mediated excitotoxicity [91].…”