title: Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria.
abstract: BACKGROUND
  Cerebral malaria (CM) is a clinical syndrome resulting from Plasmodium falciparum infection. A wide range of clinical manifestations follow the disease including cognitive dysfunction, seizures and coma. CM pathogenesis remains incompletely understood and without treatment this condition is invariably fatal. Artesunate has been accepted as the most effective drug for treating severe malaria. Besides its antiparasitic activity, an anti-inflammatory property has also been reported. In the current study, the immunomodulatory role of artesunate was investigated using a Plasmodium berghei ANKA model of CM, trough evaluation of behavioural changes and cytokines expression in hippocampus and in frontal cortex.
  
  
  METHODS
  C57Bl/6 mice were infected with P. berghei by intraperitoneal route, using a standardized inoculation of 106 parasitized erythrocytes. Memory function was evaluated using the step-down inhibitory avoidance test. The mRNA expression of IFN-γ, IL-1β, IL-6 and TNF in the frontal cortex and hippocampus of control and infected mice on day 5 post-infection were estimated by quantitative real time PCR. Plasmodium berghei -infected mice also received intraperitoneally a single dose of artesunate (32 mg/kg) on day 4 post-infection, and 24 hours after treatment behavioural and immunological analysis were performed. The protein levels of cytokines IL-2, IL-6, IL-10, IL-17, IFN-γ, TNF in the serum, frontal cortex and hippocampus of controls and P. berghei -infected mice treated or not treated with artesunate were determined using a cytometric bead array (CBA) kit. The survival and neurological symptoms of CM were also registered.
  
  
  RESULTS
  CM mice presented a significant impairment of aversive memory compared to controls on day 5 post-infection. A higher mRNA expression of pro-inflammatory cytokines was found in the hippocampus and frontal cortex of infected mice. A single dose of artesunate was also able to decrease the expression of inflammatory cytokines in the hippocampus and frontal cortex of P. berghei-infected mice. In parallel, a significant improvement in neurological symptoms and survival were observed in artesunate treated mice.
  
  
  CONCLUSIONS
  In summary, the current study provided further evidence that CM affects key brain areas related to cognition process. In addition, different patterns of cytokine expression during the course of CM could be modulated by a single administration of the anti-malarial artesunate.
authors.affiliation: Programme in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. mirandas.aline@gmail.com.
authors.forename: Aline S
authors.initials: AS
authors.lastname: Miranda
authors.forename: Fátima
authors.initials: F
authors.lastname: Brant
authors.forename: Natália P
authors.initials: NP
authors.lastname: Rocha
authors.forename: Daniel
authors.initials: D
authors.lastname: Cisalpino
authors.forename: David H
authors.initials: DH
authors.lastname: Rodrigues
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Souza
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Machado
authors.forename: Milene A
authors.initials: MA
authors.lastname: Rachid
authors.forename: Antônio L
authors.initials: AL
authors.lastname: Teixeira
authors.forename: Alline C
authors.initials: AC
authors.lastname: Campos
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000962:Antimalarials / Q000008:administration & dosage; D037621:Artemisinins / Q000008:administration & dosage*; D000077332:Artesunate; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D003584:Cytological Techniques; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000473:pathology; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D000893:Anti-Inflammatory Agents; D000962:Antimalarials; D037621:Artemisinins; D016207:Cytokines; D012333:RNA, Messenger; D000077332:Artesunate