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.

Amodiaquine analogues containing NO-donor substructures: Synthesis and their preliminary evaluation as potential tools in the treatment of cerebral malaria

“…Indeed, low NO bioavailability plays a role in the pathogenesis of murine CM [10], which is associated with cerebral microcirculatory dysfunction and vasoconstriction [18]. Treatment with an NO donor, 1-[N-(3-Aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate (DPTA-NO) largely prevents the neurological syndrome and this is associated with improved cerebral vascular responses [19]. We asked whether a hybrid compound endowed with antimalarial and NO activities could improve survival in mice with late stage CM, in comparison with its lead compound presenting antimalarial activity only.…”

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

“…Treatment with iNO resulted in increased levels of plasma nitrate, and methemoglobinemia developed, but without sequelae. The fact that iNO combined with artesunate did not result in a greater reduction of Ang-2 levels compared to artesunate alone in these trials indicates that a measurable biological effect on the endothelium was not achieved with this NO dose and route of administration (69,70). A major potential limitation with iNO is that NO may not exert its expected effects systemically, rather being restricted to the lung endothelium.…”

“…In P. berghei ANKA-infected mice, treatment with the NO donor dipropylenetriamine NONOate (DPTA-NO) prevented the neurological syndrome, with increased endothelial barrier integrity and protection of the brain tissue from extravasation and petechial hemorrhaging, but it led to hypotension in mice (70). Treatment with S-nitrosylated glutathione (GSNO), an endogenous, physiological NO donor, prevented ECM development while having milder effects on blood pressure (71).…”

“…Data from animal studies suggest its main effect takes place by restoring vascular tonus and hence reversing cerebral ischemia/hypoxia (32,70). Recent research demonstrated in ECM that NO regulates Hmox-1 expression by a mechanism involving the transcription factor Nfr-2 and consequently CO production.…”

In vivo inhibition of inducible nitric oxide synthase by aminoguanidine influences free radicals production and macrophage activity in Trichinella spiralis infected low responders (C57BL/6) and high responders (BALB/c) mice

“…These reactive substances are very effective in killing infectious agents: viruses, bacteria, protozoa and fungi (Pacelli et al, 1995). The protective role of NO in Th-1-inducing parasitic infections has been widely described (Liew et al, 1990;Liew, 1993;Rajan et al, 1996;Bhattacharjee et al, 2009;Cabrales et al, 2011). It has HELMINTHOLOGIA, 49, 4: 189 -200, 2012 In vivo inhibition of inducible nitric oxide synthase by aminoguanidine influences free radicals production and macrophage activity in Trichinella spiralis infected low responders (C57BL/6) and high responders (BALB/c) mice (Eisenstein et al, 1994;Rockett et al, 1994;Dai & Gottstein, 1999;Ren et al, 2008) and tissue pathology (Garside et al, 1992;Kolb & Kolb-Bachofen, 1992;Pacher et al, 2007).…”