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 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 approa...

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Bibliographic Details
Published in:	The Journal of infectious diseases Vol. 197; no. 7; pp. 1062 - 1073
Main Authors:	Taoufiq, Zacharie, Gay, Frederick, Balvanyos, Judith, Ciceron, Liliane, Tefit, Maurel, Lechat, Philippe, Mazier, Dominique
Format:	Journal Article
Language:	English
Published:	Chicago, IL The University of Chicago Press 01-04-2008 University of Chicago Press
Subjects:	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology Animals Apoptosis Biological and medical sciences Cerebral malaria Coculture Techniques Dyes Endothelial cells Endothelium, Vascular - drug effects Endothelium, Vascular - parasitology Erythrocytes Erythrocytes - parasitology Falciparum malaria Human protozoal diseases Humans Infectious diseases Malaria Medical sciences Models, Biological Molecules NF-kappa B - metabolism Parasites Parasitic diseases Parasitism Plasmodium falciparum Plasmodium falciparum - immunology Protein Kinase Inhibitors - pharmacology Protozoal diseases rho-Associated Kinases - antagonists & inhibitors rho-Associated Kinases - metabolism Infection Protozoal disease Malaria Enzyme Kinase Transferases Parasitosis
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Summary:	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
Bibliography:	ark:/67375/HXZ-4Z9B2921-R istex:2F826363ECA1A2E94F997FC64C586524A876A539 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-1899 1537-6613
DOI:	10.1086/528988