title: 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 (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.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Brandi D
authors.initials: BD
authors.lastname: Freeman
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Yuri C
authors.initials: YC
authors.lastname: Martins
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Oscar B
authors.initials: OB
authors.lastname: Akide-Ndunge
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Bruno
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Spray
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Mahalia S
authors.initials: MS
authors.lastname: Desruisseaux
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000378:metabolism; D013995:Time
chemical_list: D019332:Endothelin-1