Neuroprotective dimethyl fumarate synergizes with immunomodulatory interferon beta to provide enhanced axon protection in autoimmune neuroinflammation

Introduction: 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-beta) 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 MOG(35-55)-peptide. Murine IFN-beta was injected s.c. every other day at 10.000 IU, and DMF was provided at 15 mg/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-beta. 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. Discussion: Combination of IFN-beta 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. (C) 2014 Elsevier Inc All rights reserved.