New therapeutics for cerebral malaria: An investigation into the effect of HMG-CoA reductase inhibitors and anti-apoptotic strategies in experimental cerebral malaria.

摘要

Cerebral malaria (CM) accounts for a large proportion of the 1-3 million deaths due to Plasmodium falciparum malaria annually. CM is associated with excessive pro-inflammatory cytokines resulting from a dysregulated host response to infection. Apoptosis has also been implicated as an element of this response. The objective of this study was to examine the ability of certain FDA-approved compounds to modify deleterious host responses to infection and thus improve outcome. We examined the activity of statins (HMG-CoA reductase inhibitors) on malaria-associated inflammation in vivo, using the Plasmodium berghei ANKA murine model. This study also investigated the impact of statins upon Toll-like receptor (TLR)-mediated cytokine production in murine macrophages caused by P. falciparum glycosylphophatidylinositol and other TLR ligands. Using the same in vivo model, we also examined the efficacy of two distinct anti-apoptotic interventions: zVAD, a pan-caspase inhibitor, and Bcl-2, which prevents the release of apoptotic mediators from the mitochondria.