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

Souraud, Jean-Baptiste; Briolant, Sébastien; Dormoi, Jérôme; Mosnier, Joël; Savini, Hélène; Baret, Eric; Amalvict, Rémy; Soulard, Raoulin; Rogier, Christophe; Pradines, Bruno

doi:10.1186/1475-2875-11-13

Cited by 29 publications

(26 citation statements)

References 42 publications

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“…Even if AVA improved the in vitro activity of DHA [14], QN [13] or MQ [12], AVA acts differently in an in vivo combination with these three anti-malarial drugs. AVA significantly delays mouse death by CM and inhibits the development of CM symptoms when combined with anti-malarial drugs that, alone, had little or no effect in our ECM model, such as DHA (50% of the mice died with specific CM symptoms) or MQ, as previously described [17]. AVA does not improve the efficacy of anti-malarial drugs that have a significant effect when used alone, such as QN (no death with specific symptoms of CM).…”

Section: Discussionsupporting

confidence: 61%

“…Although the capacity of statins to strongly modify cytokine and chemokine profiles is documented [17,49], only five biomarkers were identified as being associated with this survival modification. Further studies on this therapeutic treatment scheme are required to examine whether AVA is a suitable partner for current malaria drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, AVA, used alone, failed to prevent death from cerebral malaria (CM) or to affect the parasitaemia of infected mice [16]. AVA combined with MQ led to a significant delay in mouse death and affected on the onset of CM symptoms [17]. …”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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

Dormoi

Briolant

Pascual

et al. 2013

Malar J

Self Cite

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“…Supporting this approach, a recently-published study reported that another member of the statin class, atorvastatin, given therapeutically alone had no effect on survival in a model of PbA-induced CM but that a prophylactic scheme employing atorvastatin together with mefloquine, rather than mefloquine alone, yielded significant delay in mortality and onset of CM symptoms [35]. Similarly, others [36] reported that statins failed to prevent death due to CM but had an adjuvant effect when administered with artesunate, delaying death in infected animals without a clear effect on overall mortality.…”

Section: Discussionmentioning

confidence: 99%

Statins Decrease Neuroinflammation and Prevent Cognitive Impairment after Cerebral Malaria

et al. 2012

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Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.

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“…Several therapeutics that have been successful in mouse models of severe malaria have been shown to target endothelial dysfunction, including (many of which have been mentioned above): a PAFR antagonist (UK-74,505), 67 various statins including atorvastatin 100 and lovastatin, 76 activated protein C, 101 carbon monoxide, 89 and nitric oxide 20 . Based on the experimental benefits of nitric oxide on the endothelium described above, our group is currently conducting a clinical trial in Uganda using inhaled nitric oxide as an adjunctive therapy to treat children with CM 147 , 148 .…”

Section: Conclusion: Endothelium-targeting Therapies Tailored To Pedmentioning

confidence: 99%

Contrasting pediatric and adult cerebral malaria

et al. 2013

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Malaria affects millions of people around the world and a small subset of those infected develop cerebral malaria. The clinical presentation of cerebral malaria differs between children and adults, and it has been suggested that age-related changes in the endothelial response may account for some of these differences. During cerebral malaria, parasites sequester within the brain microvasculature but do not penetrate into the brain parenchyma and yet, the infection causes severe neurological symptoms. Endothelial dysfunction is thought to play an important role in mediating these adverse clinical outcomes. During infection, the endothelium becomes activated and more permeable, which leads to increased inflammation, hemorrhages, and edema in the surrounding tissue. We hypothesize that post-natal developmental changes, occurring in both endothelial response and the neurovascular unit, account for the differences observed in the clinical presentations of cerebral malaria in children compared with adults.

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

Cited by 29 publications

References 42 publications

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

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

Statins Decrease Neuroinflammation and Prevent Cognitive Impairment after Cerebral Malaria

Contrasting pediatric and adult cerebral malaria

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