Morphological characteristics of intracerebral arterioles in clinical (Plasmodium falciparum) and experimental (Plasmodium berghei) cerebral malaria

Polder, Theo W.; Jerusalem, C; Eling, W.M.C.

doi:10.1016/0022-510x(91)90016-z

Cited by 26 publications

(19 citation statements)

References 23 publications

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“…8 Other findings suggestive of hypoperfusion such as increased cerebrovascular resistance, 13 intracranial hypertension, hypovolemia, systemic hypotension, acidosis, and ischemic damage are associated with poor outcomes in human CM, 4,11,18,53 and interventions that improve cerebral perfusion have been proposed to be beneficial. 8,18 Definitive evidence of cerebral vasoconstriction in human CM is lacking, although histological findings suggestive of arteriolar spasm have been described in both human and murine CM, 54 and raised serum levels of vasoconstrictive factors such as endothelin-1 have been associated with human and murine CM. [35][36][37] It is also noteworthy that TNF-␣, which is believed to play an important role in murine and human CM pathogenesis, 19,40 has been shown to induce constriction of pial arterioles in piglets 55 as well as vasoconstriction and reduction of cerebral blood volume in rats via an endothelin-dependent pathway.…”

Section: Discussionmentioning

confidence: 99%

Murine Cerebral Malaria Is Associated with a Vasospasm-Like Microcirculatory Dysfunction, and Survival upon Rescue Treatment Is Markedly Increased by Nimodipine

Cabrales

Zaniní

Meays

et al. 2010

The American Journal of Pathology

146

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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.

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Section: Discussionmentioning

confidence: 99%

Murine Cerebral Malaria Is Associated with a Vasospasm-Like Microcirculatory Dysfunction, and Survival upon Rescue Treatment Is Markedly Increased by Nimodipine

Cabrales

Zaniní

Meays

et al. 2010

The American Journal of Pathology

146

View full text Add to dashboard Cite

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“…In vivo studies of the retinal microcirculation of CM patients revealed vascular obstruction, hypoperfusion and intravascular filling defects (8). Endothelial dysfunction in CM has been demonstrated, with low nitric oxide (NO) bioavailability (9), elevated plasma levels of cell-free hemoglobin (10), asymmetric dimethylarginine (11), endothelin 1 (12), and angiopoietins (13), and spastic constriction of cerebral arterioles (14).…”

Section: Erebral Malaria (Cm) Is a Lethal Complication Ofmentioning

confidence: 99%

Transdermal Glyceryl Trinitrate as an Effective Adjunctive Treatment with Artemether for Late-Stage Experimental Cerebral Malaria

Orjuela-Sánchez

Ong

Zaniní

et al. 2013

Antimicrob Agents Chemother

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c Cerebral malaria (CM) is associated with low nitric oxide (NO) bioavailability, cerebrovascular constriction, occlusion, and hypoperfusion. Administration of exogenous NO partially prevents the neurological syndrome and associated vascular pathology in an experimental CM (ECM) mouse model. In this study, we evaluated the effects of transdermal glyceryl trinitrate in preventing ECM and, in combination with artemether, rescuing late-stage ECM mice from mortality. The glyceryl trinitrate and/or artemether effect on survival and clinical recovery was evaluated in C57BL/6 mice infected with P. berghei ANKA. NO synthase (NOS) expression in mouse brain was determined by Western blots. Mean arterial pressure (MAP) and pial arteriolar diameter were monitored using a tail-cuff blood pressure system and a cranial window preparation, respectively. Preventative administration of glyceryl trinitrate at 0.025 mg/h decreased ECM mortality from 67 to 11% and downregulated inducible NOS expression in the brain. When administered as adjunctive rescue therapy with artemether, glyceryl trinitrate increased survival from 47 to 79%. The adjunctive therapy caused a sustained reversal of pial arteriolar vasoconstriction in ECM mice, an effect not observed with artemether alone. Glyceryl trinitrate induced a 13% decrease in MAP in uninfected mice but did not further affect MAP in hypotensive ECM mice. Glyceryl trinitrate, when combined with artemether, was an effective adjunctive rescue treatment for ECM. This treatment ameliorated pial arteriolar vasospasm and did not significantly affect MAP. These results indicate that transdermal glyceryl trinitrate has potential to be considered as a candidate for adjunctive therapy for CM.

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“…The symptoms associated with CM in current mouse models include respiratory distress syndrome, decreased body temperature, and neurological manifestations characterized by ataxia, paralysis (mono-, hemi-, and tetraplegia), and coma, followed by death (10). Even though these models do not exhibit all of the features of the human syndrome (28,31), they were used to show that the sequestration of leukocytes (21) and parasitized erythrocytes (10) in the small vessels of the brain (24) and endothelial-cell damage (20,29) are involved in pathogenesis. The histopathological changes involved in both human and murine CM are characterized by loss of vascular cell integrity, tissue edema, and congestion of microvessels with parasitized erythrocytes and/or mononuclear cells (18).…”

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confidence: 99%

Susceptibility to Experimental Cerebral Malaria Induced byPlasmodium bergheiANKA in Inbred Mouse Strains Recently Derived from Wild Stock

et al. 2002

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The neurological syndrome caused by Plasmodium berghei ANKA in rodents partially mimics the human disease. Several rodent models of cerebral malaria (CM) exist for the study of the mechanisms that cause the disease. However, since common laboratory mouse strains have limited gene pools, the role of their phenotypic variations causing CM is restricted. This constitutes an obstacle for efficient genetic analysis relating to the pathogenesis of malaria. Most common laboratory mouse strains are susceptible to CM, and the same major histocompatibility complex (MHC) haplotype may exhibit different levels of susceptibility. We analyzed the influence of the MHC haplotype on overcoming CM by using MHC congenic mice with C57BL/10 and C3H backgrounds. No correlation was found between MHC molecules and the development of CM. New wild-derived mouse strains with wide genetic polymorphisms were then used to find new models of resistance to CM. Six of the twelve strains tested were resistant to CM. For two of them, F 1 progeny and backcrosses performed with the reference strain C57BL/6 showed a high level of heterogeneity in the number and characteristics of the genetic factors associated with resistance to CM.Cerebral malaria (CM) is an immunophysiopathological process caused by Plasmodium falciparum in humans and Plasmodium berghei ANKA in rodents. CM causes over 2 million deaths per year, mainly in young children. The clinical features of CM are well documented, but many aspects of its pathogenesis remain unclear. A number of parameters influence the severity of CM, including the genotype (22), the transmission level of the parasite, and the age (2), immune status (6), and genetic factors (8,12,17) of the host. However, the exact roles that these factors play are still not understood.In the past, several attempts have been made to develop rodent models to study the mechanisms that lead to cerebral disease in patients with malaria. These include efforts in rats (19), golden hamsters (26), and mice (16, 25, 26) infected with either P. berghei ANKA or K173. P. berghei ANKA, isolated from Thicket rats (Grammomys surdaster) (30), can induce a neurological syndrome that partially mimics human CM in susceptible rodent laboratory strains. The symptoms associated with CM in current mouse models include respiratory distress syndrome, decreased body temperature, and neurological manifestations characterized by ataxia, paralysis (mono-, hemi-, and tetraplegia), and coma, followed by death (10). Even though these models do not exhibit all of the features of the human syndrome (28, 31), they were used to show that the sequestration of leukocytes (21) and parasitized erythrocytes (10) in the small vessels of the brain (24) and endothelial-cell damage (20,29) are involved in pathogenesis. The histopathological changes involved in both human and murine CM are characterized by loss of vascular cell integrity, tissue edema, and congestion of microvessels with parasitized erythrocytes and/or mononuclear cells (18). Sequestration has been attrib...

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Morphological characteristics of intracerebral arterioles in clinical (Plasmodium falciparum) and experimental (Plasmodium berghei) cerebral malaria

Cited by 26 publications

References 23 publications

Murine Cerebral Malaria Is Associated with a Vasospasm-Like Microcirculatory Dysfunction, and Survival upon Rescue Treatment Is Markedly Increased by Nimodipine

Murine Cerebral Malaria Is Associated with a Vasospasm-Like Microcirculatory Dysfunction, and Survival upon Rescue Treatment Is Markedly Increased by Nimodipine

Transdermal Glyceryl Trinitrate as an Effective Adjunctive Treatment with Artemether for Late-Stage Experimental Cerebral Malaria

Susceptibility to Experimental Cerebral Malaria Induced byPlasmodium bergheiANKA in Inbred Mouse Strains Recently Derived from Wild Stock

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