Antimalarial activity of crambescidin 800 and synthetic analogues against liver and blood stage of Plasmodium sp.

Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC50=490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC50 = 8.5-59 microM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC50 = 9.2 microM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.

Blood-brain barrier breakdown during cerebral malaria: suicide or murder?

Cerebral malaria, one of the most serious complications of Plasmodium falciparum infection, is characterized by the sequestration of parasitized red blood cells (PRBCs) in cerebral microvascular beds. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances, and host immune responses all play a role. Sequestration of PRBCs is mediated by different endothelial cell surface receptors, mainly ICAM-1 and CD36. In vitro studies demonstrated that PRBC adhesion to endothelial cells induces over-expression of various adhesion molecules including ICAM-1, expression of iNOS, oxidative stress and finally apoptosis in endothelial cells. In vivo studies, in humans and in mice models of cerebral malaria brought striking evidence of the implication of brain infiltrating cytotoxic effector CD8T lymphocytes in the development of murine cerebral malaria pathogenesis. These cells probably act by direct cytotoxicity against endothelial cells. Cytotoxicity and apoptosis potentially lead blood-brain-barrier disruption and could contribute to the development of cerebral malaria. We propose a key role for endothelial cells in the pathogenesis of cerebral malaria, both by suicide / apoptosis, and / or by murder / cytotoxicity.

Induction of the CD23/nitric oxide pathway in endothelial cells downregulates ICAM-1 expression and decreases cytoadherence of Plasmodium falciparum-infected erythrocytes.

Cytoadherence of parasitized red blood cells (PRBCs) to postcapillary venules and cytokine production are clearly involved in the pathogenesis of cerebral malaria. Nitric oxide and TNF-alpha have been proposed as major effector molecules both in protective and physiopathological processes during malaria infections. Nitric oxide production has been shown to be induced by engagement of CD23 antigen. This study aimed to investigate the potential role of the CD23/nitric oxide pathway in the control of the cytoadherence of PRBCs on human endothelial cells. We demonstrate that normal human lung endothelial cells (HLECs) are able to express the low affinity receptor for IgE (Fc in RII/CD23), following cell incubation with interleukin 4 or PRBCs. Ligation of the CD23 antigen by a specific anti-CD23 monoclonal antibody at the cell surface of HLECs was found to induce iNOS mRNA and protein expression, NO release and P. falciparum killing. In addition, the specific CD23-engagement on these cells also induced a significant decrease in ICAM-1 expression, an adhesion molecule implicated in PRBCs cytoadherence. These data not only described for the first time the expression of a CD23 antigen at the cell surface of endothelial cells but also suggest a possible new regulatory mechanisms via the CD23/NO pathway during malaria infection.

[Cerebral malaria, a key role for endothelial cells?]. / Neuropaludisme, quels rôles pour la cellule endothéliale?

Five to six hundred millions of people, throughout the world, suffer from malaria and more than one million die each year as a consequence, in about 20% of the cases, of cerebral malaria, an important complication of Plasmodium falciparum infection (Holding & Snow, 2001). Despite many studies, the physiopathology of these cerebral occurrences is not understood, especially concerning the intricacy and respective roles of the various mechanisms identified: sequestration of parasitized red cells in microvessels, cytokine secretion, changes in the T lymphocyte repertoire, host genetic factors driving sensitivity pathogenic factors from Plasmodium (Mazier et al., 2000).

Heptyl prodigiosin, a bacterial metabolite, is antimalarial in vivo and non-mutagenic in vitro.

Heptyl prodigiosin was purified from a culture of alpha-proteobacteria isolated from a marine tunicate collected in Zamboanga, Philippines, as part of a program to screen natural products for antiparasitic activity. An in vitro antimalarial activity similar to that of quinine was found against the chloroquine-sensitive strain Plasmodium falciparum 3D7. The in vitro antimalarial activity was about 20 times the in vitro cytotoxic activity against L5178Y mouse lymphocytes. A single subcutaneous administration of 5 and 20 mg/kg significantly extended survival of P. berghei ANKA strain-infected mice but also caused sclerotic lesions at the site of injection. A single administration by gavage of 50 mg/kg did not increase survival time. The compound was not found to be mutagenic using in vitro micromethods for the Ames Salmonella typhimurium assay and the micronucleus assay using L5178Y mouse lymphoma cells.