Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage

Taoufiq, Zacharie; Pino, Paco; N’Dilimabaka, Nadine; Arrouss, Issam; Assi, Serge-Brice; Soubrier, Florent; Rebollo, Angelita; Mazier, Dominique

doi:10.1186/1475-2875-10-52

Cited by 36 publications

(36 citation statements)

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“…It is possible that the inhibition of cholesterol synthesis by statins results in reduced parasite invasion or reduced parasite growth. Interestingly, a recent study has shown that atorvastatin treatment of endothelial cells reduced cytoadherence of Plasmodium falciparum [37].…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin

Ramakrishnan

Striepen

et al. 2013

PLoS Pathog

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Intracellular pathogens have complex metabolic interactions with their host cells to ensure a steady supply of energy and anabolic building blocks for rapid growth. Here we use the obligate intracellular parasite Toxoplasma gondii to probe this interaction for isoprenoids, abundant lipidic compounds essential to many cellular processes including signaling, trafficking, energy metabolism, and protein translation. Synthesis of precursors for isoprenoids in Apicomplexa occurs in the apicoplast and is essential. To synthesize longer isoprenoids from these precursors, T. gondii expresses a bifunctional farnesyl diphosphate/geranylgeranyl diphosphate synthase (TgFPPS). In this work we construct and characterize T. gondii null mutants for this enzyme. Surprisingly, these mutants have only a mild growth phenotype and an isoprenoid composition similar to wild type parasites. However, when extracellular, the loss of the enzyme becomes phenotypically apparent. This strongly suggests that intracellular parasite salvage FPP and/or geranylgeranyl diphosphate (GGPP) from the host. We test this hypothesis using inhibitors of host cell isoprenoid synthesis. Mammals use the mevalonate pathway, which is susceptible to statins. We document strong synergy between statin treatment and pharmacological or genetic interference with the parasite isoprenoid pathway. Mice can be cured with atorvastatin (Lipitor) from a lethal infection with the TgFPPs mutant. We propose a double-hit strategy combining inhibitors of host and parasite pathways as a novel therapeutic approach against Apicomplexan parasites.

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Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin

Ramakrishnan

Striepen

et al. 2013

PLoS Pathog

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“…Statins also directly decrease the expression of endothelial adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin [21,22]; moreover, they can prevent P. falciparum cytoadherence and endothelial damage [23];…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model

Souraud

Briolant²,

Dormoi³

et al. 2012

Malar J

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BackgroundOne of the major complications of Plasmodium falciparum infection is cerebral malaria (CM), which causes one million deaths worldwide each year, results in long-term neurological sequelae and the treatment for which is only partially effective. Statins are recognized to have an immunomodulatory action, attenuate sepsis and have a neuroprotective effect. Atorvastatin (AVA) has shown in vitro anti-malarial activity and has improved the activity of mefloquine (MQ) and quinine.MethodsThe efficiency of 40 mg/kg intraperitoneal AVA, alone or in association with MQ, was assessed in an experimental Plasmodium berghei ANKA rodent parasite model of CM and performed according to different therapeutic schemes. The effects on experimental CM were assessed through the evaluation of brain histopathological changes and neuronal apoptosis by TUNEL staining.ResultsAVA alone in the therapeutic scheme show no effect on survival, but the prophylactic scheme employing AVA associated with MQ, rather than MQ alone, led to a significant delay in mouse death and had an effect on the onset of CM symptoms and on the level of parasitaemia. Histopathological findings show a correlation between brain lesions and CM onset. A neuronal anti-apoptotic effect of AVA in the AVA + MQ combination was not shown.ConclusionsThe combination of AVA and MQ therapy led to a significant delay in mouse mortality. There were differences in the incidence, time to cerebral malaria and the level of parasitaemia when the drug combination was administered to mice. When used in combination with MQ, AVA had a relevant effect on the in vivo growth inhibition and clinical outcome of P. berghei ANKA-infected mice.

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“…This modulation may prevent the cytoadherence at concentrations higher than 0.5 μM of AVA and endothelial damage related to CM or it may inhibit diapedesis, due to its pleiotropic effects [29-31]. A dose of 0.5 μM is relevant with plasma concentrations expected in clinical observations for patients taking 80 mg of AVA daily [15].…”

Section: Discussionmentioning

confidence: 99%

Improvement of the efficacy of dihydroartemisinin with atorvastatin in an experimental cerebral malaria murine model

Dormoi

Briolant

Pascual

et al. 2013

Malar J

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BackgroundThe medical care of malaria is a clinical emergency because it may develop into severe malaria, which has a high risk of complications and death. One of the major complications of Plasmodium falciparum infections is cerebral malaria (CM), which is responsible for at least 175,000 deaths worldwide each year and has long-term neurological sequelae. Moreover, treatment for CM is only partially effective. Statins are now known to have anti-inflammatory action, to attenuate sepsis and to have neuroprotective effects. In vitro, atorvastatin (AVA) has an anti-malarial activity and has improved the activity of quinine (QN), mefloquine (MQ), and dihydroartemisinin (DHA).ObjectivesThis study had two objectives. First, the ability of AVA to enhance DHA efficacy by improving the survival rate for CM and also decreasing signs of CM was evaluated in a murine model of experimental cerebral malaria (ECM), which was designed in C57BL6/N mice. Second, the inflammatory biomarkers were assessed at D6 and D10 in mice treated by DHA and in untreated mice in which clinical signs of CM appear rapidly and death occurs before D12. Both experiments were designed with seven days of treatment with 40 mg/kg AVA combined with five days of 3 mg/kg DHA administered intraperitoneally.ResultsAVA in combination with DHA in a therapeutic scheme leads to a significant delay in mouse death, and it has an effect on the onset of CM symptoms and on the level of parasitaemia. Evaluation of the biomarkers highlights the significant difference between treated and control mice for five cytokines and chemokines (Eotaxin-CCL11, IL-13, LIX-CXCL5, MIP1b-CCL4 and MIP2) that are known to have a role in chemotaxis.ConclusionsThe combination of DHA and AVA seems to be effective as a therapeutic scheme for improving mouse survival but less effective for cytokine modulation, which is associated with protection against CM. These results call for clinical trials of AVA as an adjuvant with anti-malarial therapy, especially with artemisinin-based combination therapy, in CM treatment or prevention.

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Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage

Cited by 36 publications

References 50 publications

Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin

Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin

Atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model

Improvement of the efficacy of dihydroartemisinin with atorvastatin in an experimental cerebral malaria murine model

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