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Malaria Journal

, 12:388

First Online: 02 November 2013Received: 18 August 2013Accepted: 29 October 2013

Abstract

BackgroundCerebral 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.

MethodsC57Bl-6 mice were infected with P. berghei by intraperitoneal route, using a standardized inoculation of 10 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.

ResultsCM 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.

ConclusionsIn 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.

KeywordsMalaria Cerebral malaria Memory impairment Artesunate Cytokines Neuroinflammation AbbreviationsCNSCentral nervous system

CMCerebral malaria

CBACytometric bead array

ELISAEnzyme-linked immunosorbent assay

IFN-γInterferon-γ

IL-1βInterleukin-1 beta

IL-2Interleukin-2

IL-6Interleukin-6

IL-10Interleukin-10

IL-17Interleukin-17

RMCBSRapid murine coma and behaviour scale

SEMStandard error of the mean

SHIRPASmithKline-Harwell-Imperial College-Royal Hospital-Phenotype Assessment

TNFTumor necrosis factor

WHOWorld health organization

Electronic supplementary materialThe online version of this article doi:10.1186-1475-2875-12-388 contains supplementary material, which is available to authorized users.

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Autor: Aline S Miranda - Fátima Brant - Natália P Rocha - Daniel Cisalpino - David H Rodrigues - Danielle G Souza - Fabiana 

Fuente: https://link.springer.com/



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