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      Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

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          Abstract

          Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG 35-55 and the animals were injected daily with Ket from the seventh to the 17th day after disease induction. This early intervention with Ket significantly reduced disease prevalence and severity. The protective effect was concomitant with less NLRP3 inflammasome activation, rebalanced oxidative stress and also reduced T cell infiltration at the CNS. Even though Ket administration did not alter mast cell percentage at the CNS, it decreased the local CPA3 and CMA1 mRNA expression that are enzymes typically produced by these cells. Evaluation of the CNS-barrier permeability indicated that Ket clearly restored the permeability levels of this barrier. Ket also triggered an evident lymphadenomegaly due to accumulation of T cells that produced higher levels of encephalitogenic cytokines in response to in vitro stimulation with MOG. Altogether these findings reinforce the concept that mast cells are particularly relevant in MS immunopathogenesis and that Ket, a known stabilizer of their activity, has the potential to be used in MS control.

          Electronic supplementary material

          The online version of this article (10.1007/s13311-019-00775-8) contains supplementary material, which is available to authorized users.

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          Author and article information

          Contributors
          karen.pinke@gmail.com
          Journal
          Neurotherapeutics
          Neurotherapeutics
          Neurotherapeutics
          Springer International Publishing (Cham )
          1933-7213
          1878-7479
          28 August 2019
          January 2020
          : 17
          : 1
          : 218-234
          Affiliations
          [1 ] GRID grid.410543.7, ISNI 0000 0001 2188 478X, Department of Microbiology and Immunology, , Institute of Biosciences, São Paulo State University (UNESP), ; Rua Dr. Plinio Pinto e Silva, S/N, Distrito de Rubião Júnior, Botucatu, São Paulo 18618-691 Brazil
          [2 ] GRID grid.410543.7, ISNI 0000 0001 2188 478X, Department of Chemistry and Biochemistry, , Institute of Biosciences, São Paulo State University (UNESP), ; Botucatu, São Paulo Brazil
          [3 ] GRID grid.11899.38, ISNI 0000 0004 1937 0722, Department of Surgery, Stomatology, Pathology and Radiology, , Bauru School of Dentistry, University of São Paulo (USP), ; Bauru, São Paulo Brazil
          Article
          PMC7007452 PMC7007452 7007452 775
          10.1007/s13311-019-00775-8
          7007452
          31463682
          © The American Society for Experimental NeuroTherapeutics, Inc. 2019
          Funding
          Funded by: FundRef http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
          Award ID: 2014/00239-6
          Categories
          Original Article
          Custom metadata
          © The American Society for Experimental NeuroTherapeutics, Inc. 2020

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