title: Neuroprotective dimethyl fumarate synergizes with immunomodulatory interferon beta to provide enhanced axon protection in autoimmune neuroinflammation.
abstract: BACKGROUND
  Despite recent advances in development of treatments for multiple sclerosis, there is still an unmet need for more effective and also safe therapies. Based on the modes of action of interferon-beta (IFN-β) and dimethyl fumarate (DMF), we hypothesized that anti-inflammatory and neuroprotective effects may synergize in experimental autoimmune encephalomyelitis (EAE).
  
  
  METHODS
  EAE was induced in C57BL/6 mice by immunization with MOG35-55-peptide. Murine IFN-β was injected s.c. every other day at 10.000IU, and DMF was provided at 15mg/kg by oral gavage twice daily. Control mice received PBS injections and were treated by oral gavage with the vehicle methylcellulose. Mice were scored daily by blinded observers and histological, FACS and cytokine studies were performed to further elucidate the underlying mechanism of action.
  
  
  RESULTS
  Combination therapy significantly ameliorated EAE disease course in comparison to controls and monotherapy with IFN-β. Histological analyses showed a significant effect on axon preservation with almost twice as much axons present in inflamed lesions as compared to control. Remarkably, the effect on axonal preservation was more pronounced under combination therapy than with both monotherapies. Neither monotherapy nor combination therapy demonstrated modulation of cytokines and frequency of antigen presenting cells.
  
  
  CONCLUSIONS
  Combination of IFN-β and DMF resulted in greater beneficial effects with improved tissue protection as compared to the respective monotherapies. Further combination studies of these safe therapies in human disease are warranted.
authors.affiliation: Department of Neurology St. Josef-Hospital, Ruhr-University Bochum, Germany; International Graduate School of Neuroscience, Ruhr-University Bochum, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reick
authors.affiliation: Department of Neurology St. Josef-Hospital, Ruhr-University Bochum, Germany. Electronic address: gisa.ellrichmann@rub.de.
authors.forename: Gisa
authors.initials: G
authors.lastname: Ellrichmann
authors.affiliation: Department of Neurology St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Thöne
authors.affiliation: BiogenIdec, Inc. Cambridge, 02142 MA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.affiliation: Department of Neurology St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Saft
authors.affiliation: Department of Neurology, University of Erlangen, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Linker
authors.affiliation: Department of Neurology St. Josef-Hospital, Ruhr-University Bochum, Germany; International Graduate School of Neuroscience, Ruhr-University Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000069462:Dimethyl Fumarate; D004195:Disease Models, Animal; D004357:Drug Synergism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications* / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005650:Fumarates / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D016900:Neurofilament Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D013997:Time Factors
chemical_list: D000943:Antigens, Differentiation; D017252:CD3 Complex; D005650:Fumarates; D007155:Immunologic Factors; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins; D010446:Peptide Fragments; C036763:monocyte-macrophage differentiation antigen; C445081:myelin oligodendrocyte glycoprotein (35-55); D016899:Interferon-beta; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000069462:Dimethyl Fumarate
keywords: Combination therapy; Dimethyl fumarate; EAE; Immunomodulation; Interferon-beta; Multiple sclerosis; Neuroprotection