title: Nitric oxide protection against murine cerebral malaria is associated with improved cerebral microcirculatory physiology.
abstract: Cerebral malaria (CM) is a leading cause of death in Plasmodium falciparum infections. In the Plasmodium berghei ANKA (PbA) murine model, CM pathogenesis is associated with low nitric oxide (NO) bioavailability and brain microcirculatory complications, with a marked decrease in cerebral blood flow, vasoconstriction, vascular plugging by adherent cells, and hemorrhages. Using intravital microscopy through a closed cranial window, here we show that NO supplementation in the form of a NO donor (dipropylenetriamine NONOate [DPTA-NO]) prevented vasoconstriction and improved blood flow in pial vessels of PbA-infected mice. Arterioles and venules of smaller diameters (20-35.5 μm) showed better response to treatment than vessels of larger diameters (36-63 μm). Exogenous NO provided protection against brain hemorrhages (mean, 1.4 vs 24.5 hemorrhagic foci per section) and inflammation (mean, 2.5 vs 10.9 adherent leukocytes per 100 μm vessel length) compared with saline treatment. In conclusion, NO protection against CM is associated with improved brain microcirculatory hemodynamics and decreased vascular pathology.
authors.affiliation: La Jolla Bioengineering Institute, 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: D000475:Alkenes / Q000494:pharmacology*; D000818:Animals; D002543:Cerebral Hemorrhage / Q000517:prevention & control; D054022:Cerebrum / Q000098:blood supply*; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control; D016779:Malaria, Cerebral / Q000378:metabolism / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D010962:Plasmodium berghei; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000475:Alkenes; C453079:dipropylenetriamine-NONOate; D009569:Nitric Oxide