Inhibition of endothelial activation: a new way to treat cerebral malaria?
BACKGROUND
Malaria is still a major public health problem, partly because the pathogenesis of its major complication, cerebral malaria (CM), remains incompletely understood. However tumor necrosis factor (TNF) is thought to play a key role in the development of this neurological syndrome, as well as lymphotoxin alpha (LT).


RESULTS
Using an in vitro model of CM based on human brain-derived endothelial cells (HBEC-5i), we demonstrate the anti-inflammatory effect of LMP-420, a 2-NH2-6-Cl-9-[(5-dihydroxyboryl)-pentyl] purine that is a transcriptional inhibitor of TNF. When added before or concomitantly to TNF, LMP-420 inhibits endothelial cell (EC) activation, i.e., the up-regulation of both ICAM-1 and VCAM-1 on HBEC-5i surfaces. Subsequently, LMP-420 abolishes the cytoadherence of ICAM-1-specific Plasmodium falciparum-parasitized red blood cells on these EC. Identical but weaker effects are observed when LMP-420 is added with LT. LMP-420 also causes a dramatic reduction of HBEC-5i vesiculation induced by TNF or LT stimulation, as assessed by microparticle release.


CONCLUSIONS
These data provide evidence for a strong in vitro anti-inflammatory effect of LMP-420 and suggest that targeting host cell pathogenic mechanisms might provide a new therapeutic approach to improving the outcome of CM patients.
Wassmer
Samuel C
SC
CNRS UMR 6020, Immunopathology Group, IFR 48, Faculty of Medicine, Université de la Méditerranée, Marseille, France.
Cianciolo
George J
GJ
Combes
Valéry
V
Grau
Georges E
GE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D001896:Boron Compounds / Q000494:pharmacology; D019013:CD40 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D011684:Purine Nucleosides / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C511928:2-amino-6-chloro-9-((5-dihydroxyboryl)pentyl)purine; D000893:Anti-Inflammatory Agents; D000962:Antimalarials; D001896:Boron Compounds; D019013:CD40 Antigens; D011684:Purine Nucleosides; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1