title: The cyclooxygenase-2 pathway via the PGE₂ EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination.
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.
authors.affiliation: Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, Bethesda, Maryland, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Palumbo
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Toscano
authors.forename: Laura
authors.initials: L
authors.lastname: Parente
authors.forename: Roberto
authors.initials: R
authors.lastname: Weigert
authors.forename: Francesca
authors.initials: F
authors.lastname: Bosetti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D000068579:Celecoxib; D002614:Chelating Agents; D003471:Cuprizone; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D015232:Dinoprostone / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013449:Sulfonamides; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D003471:Cuprizone; D051546:Cyclooxygenase 2; D053148:Caspase 3; D000068579:Celecoxib; D015232:Dinoprostone