myelin-oligodendrocyte-glycoprotein-(35-55) and zileuton

Cytosolic phospholipase A2 alpha (cPLA2 alpha) is the rate-limiting enzyme for release of arachidonic acid, which is converted primarily to prostaglandins via the cyclooxygenase (COX) 1/2 pathways, and leukotrienes via the 5-lipoxygenase (LO) pathway. We utilized inhibitors of cPLA2 alpha, COX-1/2 and 5-LO to determine the potential roles of these enzymes in development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Blocking cPLA2 alpha prevented EAE development and greatly reduced antigen-induced production of Th1-type cytokines and IL-17. Blocking COX-1/2 delayed onset and reduced severity of EAE, and reduced production of Th1-type cytokines, but not IL-17. Blocking 5-LO delayed onset and reduced cumulative severity of EAE, but did not reduce production of Th1-type cytokines or IL-17. Finally, blockade of cPLA2 alpha from the onset of clinical EAE reduced duration of EAE relapses. Therefore, cPLA2 alpha represents a potential therapeutic target for treatment of MS.

Topics: Analysis of Variance; Animals; Benzoates; Cell Proliferation; Cells, Cultured; Cyclooxygenase Inhibitors; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Glycoproteins; Group IV Phospholipases A2; Hydroxyurea; Lipoxygenase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Myelin-Oligodendrocyte Glycoprotein; Naproxen; Peptide Fragments; Severity of Illness Index; Seveso Accidental Release; Sulfonamides; Th1 Cells; Time Factors