title: Defibrotide interferes with several steps of the coagulation-inflammation cycle and exhibits therapeutic potential to treat severe malaria.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  Therapeutic use of DF in malaria is proposed.
authors: 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
authors: Ivo M B
authors: IM
authors: Francischetti
authors: Carlo J
authors: CJ
authors: Oliveira
authors: Graciela R
authors: GR
authors: Ostera
authors: Stephanie B
authors: SB
authors: Yager
authors: Françoise
authors: F
authors: Debierre-Grockiego
authors: Vanessa
authors: V
authors: Carregaro
authors: Giovanna
authors: G
authors: Jaramillo-Gutierrez
authors: Jen C C
authors: JC
authors: Hume
authors: Lubin
authors: L
authors: Jiang
authors: Samuel E
authors: SE
authors: Moretz
authors: Christina K
authors: CK
authors: Lin
authors: José M C
authors: JM
authors: Ribeiro
authors: Carole A
authors: CA
authors: Long
authors: Brandi K
authors: BK
authors: Vickers
authors: Ralph T
authors: RT
authors: Schwarz
authors: Karl B
authors: KB
authors: Seydel
authors: Massimo
authors: M
authors: Iacobelli
authors: Hans C
authors: HC
authors: Ackerman
authors: Prakash
authors: P
authors: Srinivasan
authors: Regis B
authors: RB
authors: Gomes
authors: Xunde
authors: X
authors: Wang
authors: Robson Q
authors: RQ
authors: Monteiro
authors: Michail
authors: M
authors: Kotsyfakis
authors: Anderson
authors: A
authors: Sá-Nunes
authors: Michael
authors: M
authors: Waisberg
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D016779:Malaria, Cerebral / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects* / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D010974:Platelet Aggregation / Q000187:drug effects; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D012720:Severity of Illness Index; D013925:Thromboplastin / Q000378:metabolism; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D000962:Antimalarials; D016207:Cytokines; D017261:Glycosylphosphatidylinositols; D006454:Hemoglobins; D018836:Inflammation Mediators; D011089:Polydeoxyribonucleotides; D018047:Receptors, Purinergic P1; D009569:Nitric Oxide; C036901:defibrotide; D013925:Thromboplastin