Back to Search
Start Over
Rho kinase inhibition in severe malaria: thwarting parasite-induced collateral damage to endothelia.
- Source :
-
The Journal of infectious diseases [J Infect Dis] 2008 Apr 01; Vol. 197 (7), pp. 1062-73. - Publication Year :
- 2008
-
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-kappaB 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.
- Subjects :
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine pharmacology
Animals
Coculture Techniques
Endothelium, Vascular drug effects
Erythrocytes parasitology
Humans
Models, Biological
NF-kappa B metabolism
Protein Kinase Inhibitors pharmacology
Apoptosis
Endothelium, Vascular parasitology
Plasmodium falciparum immunology
rho-Associated Kinases antagonists & inhibitors
rho-Associated Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1899
- Volume :
- 197
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 18419473
- Full Text :
- https://doi.org/10.1086/528988