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.

Microglial inhibition of neuroprotection by antagonists of the EP1 prostaglandin E2 receptor.

BACKGROUND: The EP1 receptor for the prostanoid PGE2 is a G-protein coupled receptor that has been shown to contribute to excitotoxic neuronal death. In this study we examined the influence of non-neuronal cells on neuroprotective properties of EP1 receptor antagonists (Ono 8711 and SC 51089). METHODS: Primary neuronal cultures systems with or without non-neuronal cells were used to examine how the neuroprotective properties of EP1 antagonists were influenced by non-neuronal cells. The influence of astrocytes or microglia were individually tested in excitotoxicity assays using a co-culture system with these cells grown on permeable transwell inserts above the neuronal-enriched cultures. The influence of microglia on PGE2 synthesis and EP1 receptor expression was examined. RESULTS: EP1 antagonists were neuroprotective in neuronal-enriched cultures (> 90% neurons) but not in mixed cultures (30% neurons plus other non-neuronal cells). Co-cultures of microglia on permeable transwell inserts above neuronal-enriched cultures blocked neuroprotection by EP1 antagonists. Incubation of microglia with neuronal-enriched cultures for 48 hours prior to NMDA challenge was sufficient to block neuroprotection by EP1 antagonists. The loss of neuroprotection by EP1 antagonists was accompanied by a decrease of neuronal EP1 expression in the nucleus in cultures with microglia present. CONCLUSION: These findings demonstrate microglial modulation of neuronal excitotoxicity through interaction with the EP1 receptor and may have important implications in vivo where microglia are associated with neuronal injury.

Long-term daclizumab therapy in relapsing-remitting multiple sclerosis.

We performed a retrospective review of side effects and clinical outcomes in relapsing-remitting (RR) multiple sclerosis (MS) patients receiving long-term treatment with daclizumab. Twelve patients with RR MS were initially treated with daclizumab at 1 mg/kg IV, again 14 days later and then monthly treatments (average duration 42.1 months). Daclizumab dose (0.85 mg/kg to 1.5 mg/kg) was adjusted based on clinical response. Daclizumab was generally well tolerated. There was a significant reduction in relapse rate and improvement in Expanded Disability Status Scores (EDSSs) (p < 0.0001). Long-term treatment with daclizumab in RR MS patients has apparent benefit that will require formal confirmation.