Rho kinase inhibition in severe malaria: Thwarting parasite-induced collateral damage to endothelia

Abstract

Acute clinical manifestations of falciparum malaria, such as multiorgan failure and cerebral malaria, occur unpredictably and lead to coma and death within hours if left untreated. Despite the emergency administration of effective antimalarial drugs, 15%-20% of patients die. Other therapeutic approaches are therefore urgently needed. There is increasing evidence that endothelial changes play a key role in the pathogenesis of severe malaria. We therefore used coculture models to study interactions between infected erythrocytes and endothelium. We found that adhesion of Plasmodium falciparum to endothelial cells in vitro activated the Rho kinase signaling pathway, which is strongly involved in various vascular diseases. When added concomitantly with parasites, the Rho kinase inhibitor fasudil (HA-1077), a drug already in clinical use, decreased both NF-κB activation and endothelial cell apoptosis. Fasudil also helped to restore endothelial barrier integrity after P. falciparum adhesion. Rho kinase inhibition thus appears to be a promising adjunctive therapeutic approach to the management of severe human malaria. © 2008 by the Infectious Diseases Society of America. All rights reserved.