Vascular endothelial growth factor (VEGF) and lovastatin suppress the inflammatory response to Plasmodium berghei infection and protect against experimental cerebral malaria

Abstract

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, which is associated with high mortality and long-term cognitive impairment even when effective anti-parasitic treatment is administered. Supportive therapy is needed to improve both morbidity and mortality associated with this condition. In an accompanying paper, we have demonstrated that in the Plasmodium berghei ANKA (PbA) rodent model, CM can be effectively prevented by a treatment combining sub-lethal doses of lipopolysaccharide S (LPS) and vascular endothelial growth factor (VEGF). Since LPS is not suitable for human therapy, we investigated whether lovastatin would represent a suitable substitute. This compound, widely used to lower cholesterol levels in plasma, shares with LPS the ability to elicit an anti-inflammatory response by activating the Nrf-2 gene, and when given to P. berghei-infected mice prevents to some extent the onset of CM. We show here that lovastatin- and VEGF-treated mice did not develop CM and showed few signs, if any, of endothelial damage and systemic inflammation. The combination treatment was much more effective than lovastatin and VEGF alone. Immunohistochemistry and gene expression analysis indicated that VEGF and LPS together overturned the two pathogenic mechanisms responsible for the development of CM: endothelial damage and disregulated activation of the inflammatory response. These findings provide the rationale for investigating the therapeutic potential of these compounds in human CM as well as in other inflammatory pathologies that respond poorly to steroid and non-steroid anti-inflammatory therapy.