Rho Kinase Inhibition in Severe Malaria: Thwarting Parasite-Induced Collateral Damage to Endothelia

Acute clinical manifestations of falciparum malaria, such as multiorgan failure and cerebral malaria, occur un-predictably 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 severemalaria. 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-B activation and endothelial cell apoptosis. Fasudil alsohelped to restore endothelial barrier integrity afterP. falciparum adhesion. Rho kinase inhibition thus appears to be a promising adjunctive therapeutic approach to the management of severe humanmalaria. An estimated 500 million clinical cases of malaria occur each year, and more than a million people die from com-plications of Plasmodium falciparum infection [1]. Young children and pregnant women in sub-Sahara