title: Endothelin-1 Treatment Induces an Experimental Cerebral Malaria-Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65.
abstract: Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 106PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Yuri C
authors.initials: YC
authors.lastname: Martins
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Brandi D
authors.initials: BD
authors.lastname: Freeman
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Oscar B
authors.initials: OB
authors.lastname: Akide Ndunge
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. Electronic address: m.desruis@einstein.yu.edu.
authors.forename: Mahalia S
authors.initials: MS
authors.lastname: Desruisseaux
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002448:Cell Adhesion; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000009:adverse effects* / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D007962:Leukocytes / Q000473:pathology; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia; D010962:Plasmodium berghei / Q000502:physiology*
chemical_list: D019332:Endothelin-1