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.

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

“…45,50 -53 The multifocal hypoxic areas are likely the outcome of cerebral cytoadhesion and vasospasms often seen in murine CM. 2,28,31,32,41,54 In particular, the olfactory lobe and the brainstem were affected with hypoxia.…”

“…50 Furthermore, IHC enabled us to obtain detailed information about the perivascular expression pattern and to pinpoint neuronal and perivascular hypoxia due to cerebral hypoperfusion. Considered together with the bulk of data on hypoperfusion in murine and human CM, 15,17,20,23,25,28,76 this new approach seems appropriate for further mechanistic research. The results overall suggest that cerebral hypoperfusion leads to tissue hypoxia in murine CM and that this is likely a key event in development of acute cerebral disease.…”

“…26,27 Recently, in the Plasmodium berghei ANKA (PbA) mouse model of CM, intravital microscopy demonstrated cells plugging cerebral vessels, leading to markedly decreased cerebral blood flow. 28 Vasospasms are detected in both human and murine CM, which may contribute to cerebral hypoperfusion along with cell-mediated congestion. 28 -32 Improving hypoperfusion and ischemia by increasing the oxygenation of the cerebral tissue might improve the outcome of severe malaria.…”

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

“…All the compounds are able, in different degree, to dilate pre-contracted rat aorta strips with a NO-dependent mechanism, and consequently they could be capable to help restoring the vascular homeostasis which is deeply compromised in CM. 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].…”

“…CM was defined as the presentation of one or more of the following clinical signs of neurological involvement: ataxia, limb paralysis, poor righting reflex, seizures, roll-over, coma. Additional clinical evaluation was performed using a set of six simple behavioral tests, as described [18]. Mice with late stage CM were treated with either amodiaquine (AQ) at 1mg per mouse, compound 40 or compound 31 at molar-equivalent doses (1.4mg and 1.15mg per mouse, respectively) daily for 5 days.…”