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

Abstract

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.

Dihydroartemisinin Ameliorates Learning and Memory in Alzheimer’s Disease Through Promoting Autophagosome-Lysosome Fusion and Autolysosomal Degradation for Aβ Clearance

“…One research has shown that DHA could be liable to penetrate the brain-blood barrier (Xie et al, 2009). In addition, low doses of DHA have beneficial effects on brain diseases, for example, experimental cerebral malaria in mice (Dormoi et al, 2013). In the present study, we used DHA to treat APP/PS1 double transgenic AD mice and AD model cells, intending to investigate whether DHA would maintain Aβ related production and degradation balance via promoting autophagy flux and exert a protective effect in AD.…”

Sensitivity of <I>Plasmodium falciparum</I> to Antimalarial Drugs in Hainan Island, China

“…Therefore, combination of these 2 drugs has a synergistic effect, shorter course, and reduced drug dosage and toxicity [ 18 ]. The study of Jérôme Dormoi et al [ 19 ] also showed that atorvastatin in combination with dihydroartemisinin in a therapeutic scheme leads to a significant delay in mouse death, and it has an effect on the onset of cerebral malaria symptoms and on the level of parasitemia.…”

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

“…At the same time, signs of inflammation (increased pro-inflammatory cytokines and chemokines) and endothelial dysregulation become prominent. Under conditions where antimalarial treatment only partially reverses the course of illness, additional treatment with a statin (204)(205)(206) or another intervention (207,208) that affects endothelial cells reduces neuroinflammation, restores endothelial barrier integrity, and increases survival. Dysregulation of the Angpt/Tie2 signaling axis is also seen in experimental P. berghei infection (32,(209)(210)(211).…”