title: Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis.
abstract: BACKGROUND
  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 the overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE).
  
  
  METHODS
  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.
  
  
  RESULTS
  We demonstrate that compound [2-(4-acetylphenoxy)-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one; designated as EI-03] bound to the 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) while increasing regulatory T cell development. Most importantly, mice treated with this newly identified compound exhibited reduced clinical symptoms of EAE in mouse models.
  
  
  CONCLUSIONS
  Taken together, we have identified a new compound which displays a potential therapeutic benefit for treatment of MS by targeting E-FABP.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue, NE, Austin, MN, 55912, USA. erao@hi.umn.edu.
authors.forename: Enyu
authors.initials: E
authors.lastname: Rao
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue, NE, Austin, MN, 55912, USA. psingh@hi.umn.edu.
authors.forename: Puja
authors.initials: P
authors.lastname: Singh
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue, NE, Austin, MN, 55912, USA. yli@hi.umn.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue, NE, Austin, MN, 55912, USA. yzhang@hi.umn.edu.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue, NE, Austin, MN, 55912, USA. ychi@hi.umn.edu.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Chi
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, 319 Abraham Flexner Way, Louisville, KY, 40202, USA. jill.suttles@louisville.edu.
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue, NE, Austin, MN, 55912, USA. bli@hi.umn.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D016207:Cytokines; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins