title: Murine cerebral malaria is associated with a vasospasm-like microcirculatory dysfunction, and survival upon rescue treatment is markedly increased by nimodipine.
abstract: Brain hemodynamics in cerebral malaria (CM) is poorly understood, with apparently conflicting data showing microcirculatory hypoperfusion and normal or even increased blood flow in large arteries. Using intravital microscopy to assess the pial microvasculature through a closed cranial window in the murine model of CM by Plasmodium berghei ANKA, we show that murine CM is associated with marked decreases (mean: 60%) of pial arteriolar blood flow attributable to vasoconstriction and decreased blood velocity. Leukocyte sequestration further decreased perfusion by narrowing luminal diameters in the affected vessels and blocking capillaries. Remarkably, vascular collapse at various degrees was observed in 44% of mice with CM, which also presented more severe vasoconstriction. Coadministration of artemether and nimodipine, a calcium channel blocker used to treat postsubarachnoid hemorrhage vasospasm, to mice presenting CM markedly increased survival compared with artemether plus vehicle only. Administration of nimodipine induced vasodilation and increased pial blood flow. We conclude that vasoconstriction and vascular collapse play a role in murine CM pathogenesis and nimodipine holds potential as adjunctive therapy for CM.
authors.affiliation: La Jolla Bioengineering Institute, 505 Coast Boulevard South Suite 406, La Jolla, CA 92037, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.forename: Graziela M
authors.initials: GM
authors.lastname: Zanini
authors.forename: Diana
authors.initials: D
authors.lastname: Meays
authors.forename: John A
authors.initials: JA
authors.lastname: Frangos
authors.forename: Leonardo J M
authors.initials: LJ
authors.lastname: Carvalho
mesh_terms: D000818:Animals; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D001160:Arterioles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001831:Body Temperature / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000469:parasitology; D016779:Malaria, Cerebral / Q000150:complications / Q000188:drug therapy* / Q000469:parasitology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology / Q000627:therapeutic use*; D018512:Parasitemia / Q000150:complications / Q000188:drug therapy / Q000469:parasitology / Q000503:physiopathology; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D016019:Survival Analysis; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000150:complications / Q000188:drug therapy* / Q000469:parasitology / Q000503:physiopathology*
chemical_list: D037621:Artemisinins; D009553:Nimodipine; D000077549:Artemether