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      Effects of astaxanthin in mice acutely infected with Trypanosoma cruzi Translated title: Effets de l’astaxanthine chez la souris infectée par Trypanosoma cruzi

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          During Trypanosoma cruzi infection, oxidative stress is considered a contributing factor for dilated cardiomyopathy development. In this study, the effects of astaxanthin (ASTX) were evaluated as an alternative drug treatment for Chagas disease in a mouse model during the acute infection phase, given its anti-inflammatory, immunomodulating, and anti-oxidative properties. ASTX was tested in vitro in parasites grown axenically and in co-culture with Vero cells. In vivo tests were performed in BALB/c mice (4–6 weeks old) infected with Trypanosoma cruzi and supplemented with ASTX (10 mg/kg/day) and/or nifurtimox (NFMX; 100 mg/kg/day). Results show that ASTX has some detrimental effects on axenically cultured parasites, but not when cultured with mammalian cell monolayers. In vivo, ASTX did not have any therapeutic value against acute Trypanosoma cruzi infection, used either alone or in combination with NFMX. Infected animals treated with NFMX or ASTX/NFMX survived the experimental period (60 days), while infected animals treated only with ASTX died before day 30 post-infection. ASTX did not show any effect on the control of parasitemia; however, it was associated with an increment in focal heart lymphoplasmacytic infiltration, a reduced number of amastigote nests in cardiac tissue, and less hyperplasic spleen follicles when compared to control groups. Unexpectedly, ASTX showed a negative effect in infected animals co-treated with NFMX. An increment in parasitemia duration was observed, possibly due to ASTX blocking of free radicals, an anti-parasitic mechanism of NFMX. In conclusion, astaxanthin is not recommended during the acute phase of Chagas disease, either alone or in combination with nifurtimox.

          Translated abstract

          Pendant l’infection par Trypanosoma cruzi, le stress oxydatif est considéré comme un facteur contribuant au développement de la cardiomyopathie dilatée. Dans cette étude, les effets de l’astaxanthine (ASTX) ont été évalués comme un traitement médicamenteux alternatif pour la maladie de Chagas chez un modèle de souris pendant la phase d’infection aiguë, compte tenu de ses propriétés anti-inflammatoires, immunomodulantes et anti-oxydantes. L’ASTX a été testée in vitro sur des parasites cultivés axéniquement et en co-culture avec des cellules Vero. Des tests in vivo ont été effectués chez des souris BALB/c (âgées de 4-6 semaines) infectées par T. cruzi et traitées par ASTX (10 mg/kg/jour) et/ou nifurtimox (NFMX, 100 mg/kg/jour). Les résultats montrent que l’ASTX a des effets néfastes sur les parasites cultivés axéniquement, mais pas lorsqu’ils sont cultivés avec des monocouches de cellules de mammifères. In vivo, l’ASTX n’a eu aucune valeur thérapeutique contre l’infection aiguë par T. cruzi, utilisée seule ou en association avec NFMX. Les animaux infectés traités par NFMX ou ASTX/NFMX ont survécu à la période expérimentale (60 jours), tandis que les animaux infectés traités uniquement avec ASTX sont morts avant le 30ème jour après l’infection. L’ASTX n’a montré aucun effet sur le contrôle de la parasitémie; cependant, elle a été associée à une augmentation de l’infiltration focale lymphoplasmocytaire du cœur, un nombre réduit de nids d’amastigotes dans le tissu cardiaque et à des follicules de la rate moins hyperplasiques par rapport aux groupes témoins. De manière inattendue, l’ASTX a montré un effet négatif chez les animaux infectés co-traités avec NFMX. Une augmentation de la durée de la parasitémie a été observée, probablement due au blocage par l’ASTX des radicaux libres, un mécanisme antiparasitaire du NFMX. En conclusion, l’astaxanthine n’est pas recommandée pendant la phase aiguë de la maladie de Chagas, seule ou en association avec le nifurtimox.

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          Most cited references 41

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          Chagas heart disease pathogenesis: one mechanism or many?

          Chagas heart disease (CHD), caused by the protozoan parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis in the world. The etiology of CHD is unclear and multiple mechanisms have been proposed to explain the pathogenesis of the disease. This review describes the proposed mechanisms of CHD pathogenesis and evaluates the historical significance and evidence supporting each. Although the majority of CHD-related pathologies are currently attributed to parasite persistence in the myocardium and autoimmunity, there is strong evidence that CHD develops as a result of additive and even synergistic effects of several distinct mechanisms rather than one factor.
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            Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host.

            Current knowledge of the biochemistry of Trypanosoma cruzi has led to the development of new drugs and the understanding of their mode of action. Some trypanocidal drugs such as nifurtimox and benznidazole act through free radical generation during their metabolism. T. cruzi is very susceptible to the cell damage induced by these metabolites because enzymes scavenging free radicals are absent or have very low activities in the parasite. Another potential target is the biosynthetic pathway of glutathione and trypanothione, the low molecular weight thiol found exclusively in trypanosomatids. These thiols scavenge free radicals and participate in the conjugation and detoxication of numerous drugs. Inhibition of this key pathway could render the parasite much more susceptible to the toxic action of drugs such as nifurtimox and benznidazole without affecting the host significantly. Other drugs such as allopurinol and purine analogs inhibit purine transport in T. cruzi, which cannot synthesize purines de novo. Nitroimidazole derivatives such as itraconazole inhibit sterol metabolism. The parasite's respiratory chain is another potential therapeutic target because of its many differences with the host enzyme complexes. The pharmacological modulation of the host's immune response against T. cruzi infection as a possible chemotherapeutic target is discussed. A large set of chemicals of plant origin and a few animal metabolites active against T. cruzi are enumerated and their likely modes of action are briefly discussed.
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              Development of resazurin microtiter assay for drug sensibility testing of Trypanosoma cruzi epimastigotes.

              A quantitative colorimetric assay using the oxidation-reduction indicator resazurin was developed to measure cytotoxicity of compounds against the protozoan parasite Trypanosoma cruzi. This method is based on the detection of colorimetric changes caused by the oxidation (blue) and reduction (pink) capabilities of resazurin dye, an indicator for metabolic cell function. To validate the assay, the experimental conditions were adjusted, such as number of parasites, dye concentration, and time of incubation, with respect to linearity and lower limit of detection. We found that absorbances increased linearly, with the plating density of parasites as low as 5-100 x 10(4)/well (r=0.99; p<0.001) when they were incubated for 5 h at 28 degrees C in the presence of 10% resazurin solution (3 mM). When the cytotoxicity of the reference drugs nifurtimox and benznidazole was measured with this assay and compared to the microscopic counting method, the same range was obtained, demonstrating that the resazurin microtiter assay is valid for the screening of new trypanocidal compounds. This test is very simple, fast, sensitive, and cheap.

                Author and article information

                EDP Sciences
                31 May 2017
                : 24
                : ( publisher-idID: parasite/2017/01 )
                [1 ] Centro de Investigación y Estudios Avanzados en Salud Animal, Facultad de Medicina Veterinaria y Zootecnia (FMVZ), Universidad Autónoma del Estado de México (UAEM) Kilómetro 15.5 Carretera Panamericana Toluca-Atlacomulco C.P. 50200 Toluca Estado de México
                [2 ] Facultad de Medicina, Universidad Autónoma del Estado de México, Avenida Paseo Tollocan S/N, Moderna de la Cruz C.P. 50180 Toluca de Lerdo Estado de México
                [3 ] Escuela Superior de Apan de la Universidad Autónoma del Estado de Hidalgo. Carr. Apan-Calpulalpan Km. 8, Chimalpa, Tlalayote S/N, Colonia Chimalpa Apan Hidalgo México
                [4 ] Hospital Veterinario de Pequeñas Especies, Facultad de Medicina Veterinaria y Zootecnia (FMVZ), Universidad Autónoma del Estado de México, Jesús Carranza No. 203, Universidad 50130 Toluca de Lerdo México
                Author notes
                [* ]Corresponding author: jcvch@ 123456yahoo.com
                parasite170020 10.1051/parasite/2017018
                © J.M.E. Contreras-Ortiz et al., published by EDP Sciences, 2017

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 3, Equations: 0, References: 53, Pages: 11
                Research Article


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