Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

Helmers, Andrew; Gowda, D. Channe; Kain, Kevin C.; Liles, W. Conrad

doi:10.4269/ajtmh.2009.09-0204

Cited by 13 publications

(13 citation statements)

References 46 publications

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“…treatment shows no effect on the incidence of cerebral malaria or parasitaemia, as previously described [37]. Several statins, such as simvastatin, pravastatin and fluvastatin, used alone are ineffective in cerebral malaria and have no effect on the incidence of parasitaemia during experimental malaria [30,37,38]. In the prophylactic scheme, AVA associated with MQ versus MQ alone leads to a significant delay in mouse death and has an effect on the onset of CM symptoms and on the level of parasitaemia.…”

Section: Discussionmentioning

confidence: 77%

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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Section: Discussionmentioning

confidence: 77%

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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“…Atorvastatin was shown to be 10 times more active against P. falciparum compared to mevastatin, simvastatin, lovastatin, fluvastatin or pravastatin [36], suggesting that atorvastatin is the best candidate among statins for therapy prospects in malaria treatment. Simvastatin was also used in mouse model of cerebral malaria (C57BL/6 mice infected with Plasmodium berghei ), but failed to decrease significantly parasitemia or to prevent death [38,39]. Atorvastatin may have a beneficial effect on mice survival, only when administered in combination with artesunate [40].…”

Section: Resultsmentioning

confidence: 99%

Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage

Taoufiq

Pino

N’Dilimabaka

et al. 2011

Malar J

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BackgroundThe adhesion of Plasmodium falciparum parasitized red blood cell (PRBC) to human endothelial cells (EC) induces inflammatory processes, coagulation cascades, oxidative stress and apoptosis. These pathological processes are suspected to be responsible for the blood-brain-barrier and other organs' endothelial dysfunctions observed in fatal cases of malaria. Atorvastatin, a drug that belongs to the lowering cholesterol molecule family of statins, has been shown to ameliorate endothelial functions and is widely used in patients with cardiovascular disorders.MethodsThe effect of this compound on PRBC induced endothelial impairments was assessed using endothelial co-culture models.ResultsAtorvastatin pre-treatment of EC was found to reduce the expression of adhesion molecules and P. falciparum cytoadherence, to protect cells against PRBC-induced apoptosis and to enhance endothelial monolayer integrity during co-incubation with parasites.ConclusionsThese results might suggest a potential interest use of atorvastatin as a protective treatment to interfere with the pathophysiological cascades leading to severe malaria.

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“…Most of these statin treatments tested in murine ECM were not evaluated with or compared to effective anti-malarial drugs in the context of use in treatment of human falciparum malaria [101]–[104]. Rather, these statins were assessed for their anti-parasitic properties against P. berghei ANKA in murine ECM [101]–[104]. For example, simvastatin was evaluated for its effect on parasitemia during murine ECM with no comparison with an effective anti-malarial drug [101], [102].…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Inhibition of CXCL10 in Combination with Anti-malarial Therapy Eliminates Mortality Associated with Murine Model of Cerebral Malaria

et al. 2013

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Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients.

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Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

Cited by 13 publications

References 46 publications

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

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

Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage

Pharmacologic Inhibition of CXCL10 in Combination with Anti-malarial Therapy Eliminates Mortality Associated with Murine Model of Cerebral Malaria

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