RESUMEN
Apolipoprotein E (ApoE) is the major ligand for the transporting and removal of chylomicrons and lipoproteins by the liver. Since the creation of the ApoE-knockout mice, it is well established that ApoE deficiency results in spontaneous atherosclerosis in aged animals. Atherosclerosis is also observed in animals infected with Trypanosoma cruzi, a protozoan that elicits a systemic inflammatory response in mammalian hosts, culminating in damage to cardiac, neuronal, and endothelial cells. Pro-atherogenic effects related to the experimental infection with T. cruzi may be induced by inflammatory components affecting the vascular wall. Herein, we evaluated whether infection with different strains of T. cruzi worsened the atherogenic lesions observed in aged ApoE-/- mice. After four weeks of infection with Berenice-78 (Be-78) or Colombian (Col) strains of the parasite, mice presented increased CCL2 and CCL5 production and high migration of inflammatory cells to cardiac tissue. Although the infection with either strain did not affect the survival rate, only the infection with Col strain caused abundant parasite growth in blood and heart and increased aortic root lesions in ApoE-/- mice. Our findings show, for the first time that ApoE exerts a protective anti-atherosclerotic role in the aortic root of mice in the acute phase of experimental infection with the Col strain of T. cruzi. Further studies should target ApoE and nutritional interventions to modulate susceptibility to cardiovascular disabilities after T. cruzi infection, minimizing the risk of death in both experimental animals and humans.
Asunto(s)
Apolipoproteínas E , Aterosclerosis , Enfermedad de Chagas , Trypanosoma cruzi , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/complicaciones , Aterosclerosis/patología , Enfermedad de Chagas/complicaciones , Quilomicrones , Células Endoteliales/patología , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
OBJECTIVE: Trypanosoma cruzi infection affects millions of people worldwide, and the drugs available for its treatment have limited efficacy. 1,8-Dioxooctahydroxanthenes and tetraketones are compounds with important biological applications. The aim of this study was to assess the trypanocidal and inflammatory activities of nine 1,8-dioxooctahydroxanthenes (1-9) and three tetraketones (10-12). METHODS AND RESULTS: By in vitro killing assay, three compounds were able to eliminate CL TdTomato expressing strain of T. cruzi, 9 (IC50=30.65µM), 10 (IC50=14.11µM), and 11 (IC50=26.43µM). However, only 9 was not toxic to Vero cells. Next, to evaluate the in vivo antitrypanosomal and immunological efficacy of 9, Swiss mice were infected with the Y and CL strains of T. cruzi and treated for 10 days with 50mg/kg of 9. This compound reduced the cardiac inflammatory infiltration in animals infected with both strains. Rank's ligand (RankL), CCL2, and interferon (IFN)-γ were measured in the cardiac tissue homogenate of the Y-strain-infected animals, and no interference of 9 was observed. However, compound 9 increased the RankL and interleukin (IL)-10 levels in CL-infected mice. No hepatic and renal toxicity was observed. CONCLUSION: Our findings showed that 1,8-dioxooctahydroxanthene has antiparasitic effect and ameliorates the cardiac inflammatory parameters related to T. cruzi infection.
Asunto(s)
Enfermedad de Chagas , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Animales , Enfermedad de Chagas/tratamiento farmacológico , Chlorocebus aethiops , Ratones , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Células VeroRESUMEN
BACKGROUND The infection led by Trypanosoma cruzi persists in mammalian tissues causing an inflammatory imbalance. Carvedilol (Cv), a non-selective beta blocker drug indicated to treat heart failure and antihypertensive has shown to promote antioxidant and immunomodulatory properties which might improve the inflammation induced by T. cruzi. OBJECTIVES Evaluate the role of Cv on the inflammatory response of C57BL/6 mice acutely infected with the Colombian strain of T. cruzi. METHODS Animals were infected with the Colombian strain of T. cruzi and treated with Cv (25 mg/kg/day), benznidazole (Bz) (100 mg/kg/day) or their combination. On the 28th day of infection and 23 days of treatment, the euthanasia occurred, and the heart preserved for histopathological, oxidative stress (SOD, catalase, TBARs, carbonylated proteins) and plasma (CCL2, CCL5, TNF, IL-10) analyses. Parasitaemia and survival were assessed along the infection. FINDINGS Cv decreased TBARs, but increased the mortality rate, the parasitaemia and the levels of CCL2, CCL5, catalase and the inflammatory infiltrate in the cardiac tissue. Bz led the reduction of the inflammatory infiltrate and circulating levels of oxidative stress and inflammatory mediators in the infected mice. MAIN CONCLUSIONS Our data suggest that Cv, in this experimental model using the Colombian strain of T. cruzi, caused damage to the host.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Carvedilol/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Corazón/efectos de los fármacos , Nitroimidazoles/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Enfermedad Aguda , Animales , Catalasa/análisis , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/patología , Citocinas/sangre , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Masculino , Ratones Endogámicos C57BL , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Parasitemia/parasitología , Carbonilación Proteica/efectos de los fármacos , Valores de Referencia , Reproducibilidad de los Resultados , Superóxido Dismutasa/análisis , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Factores de Tiempo , Trypanosoma cruzi/aislamiento & purificaciónRESUMEN
BACKGROUND The infection led by Trypanosoma cruzi persists in mammalian tissues causing an inflammatory imbalance. Carvedilol (Cv), a non-selective beta blocker drug indicated to treat heart failure and antihypertensive has shown to promote antioxidant and immunomodulatory properties which might improve the inflammation induced by T. cruzi. OBJECTIVES Evaluate the role of Cv on the inflammatory response of C57BL/6 mice acutely infected with the Colombian strain of T. cruzi. METHODS Animals were infected with the Colombian strain of T. cruzi and treated with Cv (25 mg/kg/day), benznidazole (Bz) (100 mg/kg/day) or their combination. On the 28th day of infection and 23 days of treatment, the euthanasia occurred, and the heart preserved for histopathological, oxidative stress (SOD, catalase, TBARs, carbonylated proteins) and plasma (CCL2, CCL5, TNF, IL-10) analyses. Parasitaemia and survival were assessed along the infection. FINDINGS Cv decreased TBARs, but increased the mortality rate, the parasitaemia and the levels of CCL2, CCL5, catalase and the inflammatory infiltrate in the cardiac tissue. Bz led the reduction of the inflammatory infiltrate and circulating levels of oxidative stress and inflammatory mediators in the infected mice. MAIN CONCLUSIONS Our data suggest that Cv, in this experimental model using the Colombian strain of T. cruzi, caused damage to the host.