title: Atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model.
abstract: BACKGROUND
  One 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  AVA 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Unité de parasitologie, Unité de recherche sur les maladies infectieuses et transmissibles émergentes - UMR 6236, Institut de recherche biomédicale des armées - antenne de Marseille, Allée du Médecin-colonel Jamot, Parc le Pharo, BP 60109, 13262 Marseille Cedex 7, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Souraud
authors.forename: Sébastien
authors.initials: S
authors.lastname: Briolant
authors.forename: Jérome
authors.initials: J
authors.lastname: Dormoi
authors.forename: Joel
authors.initials: J
authors.lastname: Mosnier
authors.forename: Hélène
authors.initials: H
authors.lastname: Savini
authors.forename: Eric
authors.initials: E
authors.lastname: Baret
authors.forename: Rémy
authors.initials: R
authors.lastname: Amalvict
authors.forename: Raoulin
authors.initials: R
authors.lastname: Soulard
authors.forename: Christophe
authors.initials: C
authors.lastname: Rogier
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D017209:Apoptosis; D000069059:Atorvastatin; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006651:Histocytochemistry; D007150:Immunohistochemistry; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015767:Mefloquine / Q000008:administration & dosage*; D051379:Mice; D009474:Neurons / Q000473:pathology; D010962:Plasmodium berghei / Q000187:drug effects* / Q000472:pathogenicity; D011758:Pyrroles / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D015767:Mefloquine