Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria

摘要: Objective— The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities successfully used to treat comatose children with veno-occlusive disease. DF was investigated here drug cerebral malaria. Methods Results— blocks tissue factor expression by ECs incubated parasitized red blood cells attenuates prothrombinase activity, platelet aggregation, complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol ( Pf -GPI) induces cytokine production dendritic cells. Notably, cells, known modulate coagulation inflammation systemically, were identified novel target for DF. Accordingly, inhibits Toll-like receptor ligand-dependent activation mechanism is blocked adenosine antagonist (8-p-sulfophenyltheophylline) but reproduced synthetic poly-A, -C, -T, -G. These results imply aptameric sequences mediate responses the drug. prevents rosetting formation, invasion P. abolishes oocysts development Anopheles gambiae. murine model malaria, affected parasitemia, decreased IFN-γ levels, ameliorated clinical score (day 5) trend increased survival. Conclusion— Therapeutic use proposed.