Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12

AUTHORS

Juliana Fraga Vasconcelos, Cássio Santana Meira, Daniela Nascimento Silva, Carolina Kymie Vasques Nonaka, Pâmela Santana Daltro, Simone Garcia Macambira, Pablo Daniel Domizi, Valéria Matos Borges, Ricardo Ribeiro-dos-Santos, Bruno Solano de Freitas Souza, Milena Botelho Pereira Soares

ABSTRACT

Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi-infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls. Serum concentrations of galectin-3, IFNγ and TNFα, as well as cardiac gene expression of inflammatory mediators were reduced after DMS treatment. The gene expression of M1 marker, iNOS, was decreased, while the M2 marker, arginase1, was increased. DMS-treated mice showed an improvement in exercise capacity. Moreover, DMS caused a reduction in parasite load in vivo. DMS inhibited the activation of lymphocytes, and reduced cytokines and NO production in activated macrophage cultures in vitro, while increasing IL-1β production. Analysis by qRT-PCR array showed that DMS treatment modulated inflammasome activation induced by T. cruzi on macrophages. Altogether, our results demonstrate that DMS, through anti-parasitic and immunomodulatory actions, can be beneficial in the treatment of chronic phase of T. cruzi infection and suggest that S1P-activated processes as possible therapeutic targets for the treatment of Chagas disease cardiomyopathy. More... »

PAGES

6171

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-06275-z

DOI

http://dx.doi.org/10.1038/s41598-017-06275-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1090754913

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28733584


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