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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Defibrotide interferes with several steps of the coagulation-inflammation cycle and exhibits therapeutic potential to treat severe malaria
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 32, No. 3, Year 2012
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Description
Objective-The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. Methods and Results-DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A,-C,-T, and-G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation, red blood cells invasion by P. falciparum and abolishes oocysts development in Anopheles gambiae. In amurine model of cerebral malaria, DF affected parasitemia, decreased IFN-γlevels, and ameliorated clinical score (day 5) with a trend for increased survival. Conclusion- Therapeutic use of DF in malaria is proposed. © 2012 American Heart Association, Inc.
Authors & Co-Authors
Francischetti, Ivo M.B.
United States, Bethesda
National Institutes of Health Nih
Ostera, Graciela R.
United States, Bethesda
National Institutes of Health Nih
Debierre-Grockiego, Françoise
Germany, Marburg
Philipps-universität Marburg
Carregaro, Vanessa
United States, Bethesda
National Institutes of Health Nih
Brazil, Sao Paulo
Universidade de São Paulo
Jaramillo-Gutierrez, Giovanna
United States, Bethesda
National Institutes of Health Nih
Hume, Jen C.C.
United States, Bethesda
National Institutes of Health Nih
United States, Seattle
Seattle Biomedical Research Institute
Jiang, Lubin
United States, Bethesda
National Institutes of Health Nih
Moretz, Samuel E.
United States, Bethesda
National Institutes of Health Nih
Ribeiro, J. M.C.
United States, Bethesda
National Institutes of Health Nih
Long, Carole A.
United States, Bethesda
National Institutes of Health Nih
Seydel, Karl B.
United States, Bethesda
National Institutes of Health Nih
Ackerman, Hans C.
United States, Bethesda
National Institutes of Health Nih
Gomes, Regis Bernardo Brandim
United States, Bethesda
National Institutes of Health Nih
Wang, Xunde
United States, Bethesda
National Institutes of Health Nih
Monteiro, Robson Q.
Brazil, Rio de Janeiro
Universidade Federal do Rio de Janeiro
Kotsyfakis, Michail
United States, Bethesda
National Institutes of Health Nih
Czech Republic, Ceske Budejovice
Biology Centre of Academy of Sciences of the Czech Republic
Sa-Nunes, Anderson
United States, Bethesda
National Institutes of Health Nih
Brazil, Sao Paulo
Universidade de São Paulo
Waisberg, Michael
United States, Bethesda
National Institutes of Health Nih
Statistics
Citations: 29
Authors: 18
Affiliations: 9
Identifiers
Doi:
10.1161/ATVBAHA.111.240291
ISSN:
15244636
Research Areas
Genetics And Genomics
Infectious Diseases
Maternal And Child Health