Cysteamine broadly improves the anti-plasmodial activity of artemisinins against murine blood stage and cerebral malariaReport as inadecuate




Cysteamine broadly improves the anti-plasmodial activity of artemisinins against murine blood stage and cerebral malaria - Download this document for free, or read online. Document in PDF available to download.

Malaria Journal

, 15:260

First Online: 06 May 2016Received: 02 November 2015Accepted: 28 April 2016DOI: 10.1186-s12936-016-1317-3

Cite this article as: Moradin, N., Torre, S., Gauthier, S. et al. Malar J 2016 15: 260. doi:10.1186-s12936-016-1317-3

Abstract

BackgroundThe potential emergence and spread of resistance to artemisinins in the Plasmodium falciparum malaria parasite constitutes a major global health threat. Hence, improving the efficacy of artemisinins and of artemisinin-based combination therapy ACT represents a major short-term goal in the global fight against malaria. Mice defective in the enzyme pantetheinase Vnn3 show increased susceptibility to blood-stage malaria increased parasitaemia, reduced survival, and supplementation of Vnn3 mutants with the reaction product of pantetheinase, cysteamine, corrects in part the malaria-susceptibility phenotype of the mutants. Cysteamine Cys is a small, naturally occurring amino-thiol that has very low toxicity in vivo and is approved for clinical use in the life-long treatment of the kidney disorder nephropathic cystinosis.

MethodsThe ability of Cys to improve the anti-plasmodial activity of different clinically used artemisinins was tested. The effect of different CYS-ART combinations on malarial phenotypes parasite blood-stage replication, overall and survival from lethal infection was assessed in a series of in vivo experiments using Plasmodium strains that induce either blood-stage Plasmodium chabaudi AS or cerebral disease Plasmodium berghei ANKA. This was also evaluated in an ex vivo experimental protocol that directly assesses the effect of such drug combinations on the viability of Plasmodium parasites, as measured by the ability of tested parasites to induce a productive infection in vivo in otherwise naïve animals.

ResultsCys is found to potentiate the anti-plasmodial activity of artesunate, artemether, and arteether, towards the blood-stage malaria parasite P. chabaudi AS. Ex vivo experiments, indicate that potentiation of the anti-plasmodial activity of artemisinins by Cys is direct and does not require the presence of host factors. In addition, potentiation occurs at sub-optimal concentrations of artemisinins and Cys that on their own have little or no effect on parasite growth. Cys also dramatically enhances the efficacy and protective effect of artemisinins against cerebral malaria induced by infection with the P. berghei ANKA parasite.

ConclusionThese findings indicate that inclusion of Cys in current formulations of ACT, or its use as adjunct therapy could improve the anti-plasmodial activity of artemisinin, decrease mortality in cerebral malaria patients, and prevent or delay the development and spread of artemisinin resistance.

KeywordsPlasmodium Blood-stage malaria Cerebral malaria Cysteamine Artemisinins Drug resistance Electronic supplementary materialThe online version of this article doi:10.1186-s12936-016-1317-3 contains supplementary material, which is available to authorized users.

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Author: Neda Moradin - Sabrina Torre - Susan Gauthier - Mifong Tam - Jalal Hawari - Kirsten Vandercruyssen - Bart De Spiegeleer - A

Source: https://link.springer.com/







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