Arachidonic acid (AA) has important physiological roles and is a key mediator of inflammation. Released from membrane glycerophospholipids by cyctosolic phospolipase-A2α (cPLA2α), AA may be further converted to prostaglandins, leukotrienes, lipoxins, and hydroxy-eicosatetraenoic acids by cyclooxygenases (COXs), lipoxygenases (LOs), and terminal enzymes.
It has already been established that cPLA2α plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), but the downstream effectors have remained elusive. Collaborators from Tokyo, Kyushu and Osaka Universities have now conducted a targeted analysis of the AA cascade in the spinal cords of naïve and EAE mice using transcriptomics and lipidomics. The lipidomics study identified constitutive generation of eicosanoids in the spinal cords of naïve mice, predominantly via the cyclooxygenase (COX) pathway, with prostaglandin-D2 (PGD2) and metabolites favoured. In EAE lesions, however, levels of prostaglandin-E2 (PGE2) and metabolites were increased while PGD2 decreased. The researchers then examined microsomal PGE synthase-1 (mPGES-1), a key enzyme involved in the production of PGE2 in inflammation. Their findings suggest that PGE2 levels in the spinal cords of EAE mice are dependent on mPGES-1 expressed in macrophages/microglia. In addition, the clinical course of EAE was less severe in mPGES-1-/- mice. Although there are currently no known, effective inhibitors of rodent mPGES-1, a potent and selective inhibitor of the human enzyme, MF63, was reported last year. In that study MF63 suppressed PGE2 production, pyresis and inflammatory pain in a knock-in mouse expressing human mPGES-1.
The authors of the present study, published in PNAS, also examined autopsy brain tissues obtained from MS patients. In agreement with the data in murine EAE, immunohistochemistry on MS lesions revealed the overt expression of mPGES-1 protein in CD68+ macrophages. These data suggest that human MS pathology also appears to be influenced by the mPGES-1/PGE2 axis of the AA cascade and that inhibition of mPGES-1 may have utility in the treatment of MS.