title: Improvement of the efficacy of dihydroartemisinin with atorvastatin in an experimental cerebral malaria murine model.
abstract: BACKGROUND
  The 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).
  
  
  OBJECTIVE
  This 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.
  
  
  RESULTS
  AVA 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Unité de Parasitologie, Département d'Infectiologie de Terrain, Institut de Recherche Biomédicale des Armées, Marseille, France. bruno.pradines@free.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Dormoi
authors.forename: Sébastien
authors.initials: S
authors.lastname: Briolant
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pascual
authors.forename: Camille
authors.initials: C
authors.lastname: Desgrouas
authors.forename: Christelle
authors.initials: C
authors.lastname: Travaillé
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage*; D000069059:Atorvastatin; D015415:Biomarkers / Q000032:analysis; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D007249:Inflammation / Q000473:pathology; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D000962:Antimalarials; D037621:Artemisinins; D015415:Biomarkers; D006538:Heptanoic Acids; D011758:Pyrroles; C039060:artenimol; D000069059:Atorvastatin