Abstract
Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.
Highlights
Malaria, caused by infection with the intraerythrocytic parasite Plasmodium falciparum, is a potentially life threatening disease, with significant morbidity and devastating economic consequences in developing countries [1]
We examined the effect of the selective endothelin type A receptor (ETA) receptor antagonist, BQ123, on uninfected and P. berghei ANKA (PbA)-infected mice
BQ123 improved disease severity and the development of neurological signs associated with Experimental CM (ECM), in PbA-infected mice, as measured by the rapid murine coma and behavior scale (RMCBS) (Fig 1C)
Summary
Malaria, caused by infection with the intraerythrocytic parasite Plasmodium falciparum, is a potentially life threatening disease, with significant morbidity and devastating economic consequences in developing countries [1]. Experimental CM (ECM) models exhibit several pathological alterations observed in human CM, including cerebral vascular obstruction, vasoconstriction, reduced cerebral blood flow (CBF), brain hemorrhage, BBB disruption, inflammation, and neurological impairment [5,6,7,8,9,10,11]. Such models enable researchers to examine the cellular and molecular mechanisms involved in CM pathology. ET-1 is associated with inflammation, microglial activation, BBB breakdown, and likely contributes to the neuroinflammatory process and ensuing neurocognitive impairment observed in CM [10, 13,14,15,16]
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