Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis (THER7P.947)

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration. Our previous studies have demonstrated that epidermal fatty acid binding protein (E-FABP) widely expressed in immune cells, in particular in dendritic cells (DCs) and T lymphocytes, fuels their overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE). In the present study, we conducted an intensive computational docking analysis to identify novel E-FABP inhibitors for regulation of immune cell functions and for treatment of EAE. We demonstrate that compound [2-(4-acetylphenoxy)-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one; designated as EI-03] binded lipid binding pocket of E-FABP and enhanced the expression of peroxisome proliferator-activating receptor (PPAR) γ. Further in vitro experiments showed that EI-03 regulated DC functions by inhibition of TNFα production while promoting IL-10 secretion. Moreover, EI-03 treatment counterregulated T cell balance by decreasing effector T cell differentiation (e.g. Th17, Th1) but increasing regulatory T cell development. Most importantly, mice treated with this newly identified compound exhibited reduced clinical symptoms of EAE in different mouse models. Taken together, we have identified a new compound which displays a potential therapeutic benefit for treatment of MS by targeting E-FABP.