Cyclooxygenases (COX)-1 and -2 are key enzymes required for the conversion of arachidonic acid to eicosanoids, potent mediators of inflammation. In patients with multiple sclerosis, COX-2 derived prostaglandins (PGs) are elevated in the CSF and COX-2 is up-regulated in demyelinating plaques. However, it is not known whether COX-2 activity contributes to oligodendrocyte death. In cuprizone-induced demyelination, oligodendrocyte apoptosis and a concomitant increase in the gene expression of COX-2 and PGE₂-EP2 receptor precede histological demyelination. COX-2 and EP2 receptor were expressed by oligodendrocytes, suggesting a causative role for the COX-2/EP2 pathway in the initiation of oligodendrocyte death and demyelination. COX-2 gene deletion, chronic treatment with the COX-2 selective inhibitor celecoxib, or with the EP2 receptor antagonist AH6809 reduced cuprizone-induced oligodendrocyte apoptosis, the degree of demyelination and motor dysfunction. These data indicate that the PGE₂ EP2 receptor contributes to oligodendrocyte apoptosis and open possible new therapeutic approaches for multiple sclerosis.

The cyclooxygenase-2 pathway via the PGE 2 EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination

PALUMBO, SARA;
2012-01-01

Abstract

Cyclooxygenases (COX)-1 and -2 are key enzymes required for the conversion of arachidonic acid to eicosanoids, potent mediators of inflammation. In patients with multiple sclerosis, COX-2 derived prostaglandins (PGs) are elevated in the CSF and COX-2 is up-regulated in demyelinating plaques. However, it is not known whether COX-2 activity contributes to oligodendrocyte death. In cuprizone-induced demyelination, oligodendrocyte apoptosis and a concomitant increase in the gene expression of COX-2 and PGE₂-EP2 receptor precede histological demyelination. COX-2 and EP2 receptor were expressed by oligodendrocytes, suggesting a causative role for the COX-2/EP2 pathway in the initiation of oligodendrocyte death and demyelination. COX-2 gene deletion, chronic treatment with the COX-2 selective inhibitor celecoxib, or with the EP2 receptor antagonist AH6809 reduced cuprizone-induced oligodendrocyte apoptosis, the degree of demyelination and motor dysfunction. These data indicate that the PGE₂ EP2 receptor contributes to oligodendrocyte apoptosis and open possible new therapeutic approaches for multiple sclerosis.
2012
Palumbo, Sara; Toscano, Christopher D.; Parente, Laura; Weigert, Roberto; Bosetti, Francesca
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/772571
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