Defibrotide interferes with several steps of the coagulation-inflammation cycle and exhibits therapeutic potential to treat severe malaria.
| Autor: | Francischetti IM; Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ifrancischetti@niaid.nih.gov, Oliveira CJ, Ostera GR, Yager SB, Debierre-Grockiego F, Carregaro V, Jaramillo-Gutierrez G, Hume JC, Jiang L, Moretz SE, Lin CK, Ribeiro JM, Long CA, Vickers BK, Schwarz RT, Seydel KB, Iacobelli M, Ackerman HC, Srinivasan P, Gomes RB, Wang X, Monteiro RQ, Kotsyfakis M, Sá-Nunes A, Waisberg M |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2012 Mar; Vol. 32 (3), pp. 786-98. Date of Electronic Publication: 2011 Nov 23. |
| DOI: | 10.1161/ATVBAHA.111.240291 |
| Abstrakt: | 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 a murine model of cerebral malaria, DF affected parasitemia, decreased IFN-γ levels, and ameliorated clinical score (day 5) with a trend for increased survival. Conclusion: Therapeutic use of DF in malaria is proposed. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|