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

• DOI: 10.1371/journal.ppat.1005477
• Publication Date: 2016-03-31T17:51:03Z
• Authors: Brandi D. Freeman; Yuri C. Martins; Oscar B. Akide-Nd...; Fernando P. Bruno; Hua Wang; Herbert B. Tanowitz; David C. Spray; Mahalia S. Desrui...
• Keywords: Cerebral Malaria; Plasmodium berghei; Endothelin receptor antagonist

Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, potentially life-threatening encephalopathy. Vasculopathy is thought to contribute malaria pathogenesis. The vasoactive compound endothelin-1, key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental model, sustained memory loss. Herein, we demonstrate an endothelin type A receptor (ETA) antagonist prevented malaria-induced neurocognitive impairments improved survival. ETA antagonism blood-brain barrier disruption vasoconstriction during reduced brain endothelial activation, diminishing microvascular congestion. Furthermore, exogenous endothelin-1 administration NK65-infected mice, model generally regarded as non-cerebral negative control for ANKA infection, led malaria-like deficits. Our data indicate critical the development cerebrovascular This peptide may thus serve potential target adjunctive therapy management