Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria

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 (ET _A) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ET _A 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.

Author Summary

The parasite Plasmodium falciparum is the primary cause of cerebral malaria, a neurological manifestation of severe malaria. Cerebral malaria results in disturbances to the blood vessels of the brain, eventually leading to damage to the blood-brain barrier. This damage can lead to adverse, debilitating neurological complications, particularly in children and individuals with compromised immune systems. Yet there is still a considerable gap in understanding the causes of the detrimental neurological effects of P. falciparum infection. We employed a multidisciplinary approach to delineate the mechanisms by which Plasmodium infection causes these abnormalities. The vasoactive peptide endothelin-1 is implicated in a variety of neurological and inflammatory diseases. Using mouse experimental models of cerebral malaria, we demonstrated that targeting this protein resulted in stabilization of the blood vessels in the brain, decreased the influx of inflammatory cells to the brain vessels, and preserved the integrity of the blood-brain barrier, eventually leading to improved cognitive function and improved survival rates in mice with infection. It is our hope that our work will help extend understanding of the causes of cerebral malaria in humans, and may eventually lead to therapies for preservation or salvaging of neurological function in the management of this disease.