Anti-Trypanosoma cruzi action of a new benzofuran derivative based on amiodarone structure

Chagas disease is a neglected tropical affection caused by the protozoan parasite Trypanosoma cruzi. There is no current effective treatment since the only two available drugs have a limited efficacy and produce side effects. Thus, investigation efforts have been directed to the identification of new drug leads. In this context, Ca2+ regulating mechanisms have been postulated as targets for antiparasitic compounds, since they present paramount differences when compared to host cells. Amiodarone is an antiarrhythmic with demonstrated trypanocidal activity acting through the disruption of the parasite intracellular Ca2+ homeostasis. We now report the effect of a benzofuran derivative based on the structure of amiodarone on T. cruzi. This derivative was able to inhibit the growth of epimastigotes in culture and of amastigotes inside infected cells, the clinically relevant phase. We also show that this compound, similarly to amiodarone, disrupts Ca2+ homeostasis in T. cruzi epimastigotes, via two organelles involved in the intracellular Ca2+ regulation and the bioenergetics of the parasite. We demonstrate that the benzofuran derivative was able to totally collapse the membrane potential of the unique giant mitochondrion of the parasite and simultaneously produced the alkalinization of the acidocalcisomes. Both effects are evidenced by a large increase in the intracellular Ca2+ concentration of T. cruzi.Fil: Pinto Martinez, Andrea. instituto de Estudios Avanzados; VenezuelaFil: Hernández Rodríguez, Vanessa. instituto de Estudios Avanzados; VenezuelaFil: Rodríguez Durán, Jessica Jenireth. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. instituto de Estudios Avanzados; VenezuelaFil: Hejchman, Elżbieta. Medical University of Warsaw; PoloniaFil: Benaim, Gustavo. Universidad Central de Venezuela; Venezuel

Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach

<div><p>Abstract Background: Considering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market. Methods: In this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.)infantum and its in vitro and in vivo activity. Results: The evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20% in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR. Conclusions: Our findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.</p></div

Identification and electrophysiological properties of a sphingosine-dependent plasma membrane Ca2+ channel in Trypanosoma cruzi

Trypanosoma cruzi is the causative agent of Chagas disease. The only two drugs accepted for the treatment of this infection are benznidazole and nifurtimox, which are of limited use in the predominant chronic phase. On the search for new drugs, the intracellular Ca2+ regulation has been postulated as a possible target, due to differences found between host cells and the parasite. The mechanisms involved in the intracellular Ca2+ regulation of T. cruzi have been partially elucidated. However, nothing is known about a putative channel responsible for the Ca2+ entry into this parasite. In contrast, in Leishmania spp., a closely related hemoflagelate, a sphingosine-activated plasma membrane Ca2+ channel has been recently described. The latter resembles the L-type voltage-gated Ca2+ channel present in humans, but with distinct characteristics. This channel is one of the main targets concerning the mechanism of action of miltefosine, the unique oral drug approved against leishmaniasis. In the present work, we describe for the first time, the electrophysiological characterization of a sphingosine-activated Ca2+ channel of T. cruzi by reconstituting plasma membrane vesicles into giant liposomes and patch clamp. This channel shares some characteristic as activation by Bay K8644 and inhibition by channel blockers such as nifedipine. However, the T. cruzi channel differs from the L-type VGCC in its activation by sphingosine and/or miltefosine. Albeit the conductance for each, Ba2+, Ca2+ and Sr2+ was similar, the parasite channel appears not to be voltage dependent. A gene that presents homology in critical amino acids with its human ortholog Ca2+ channel was identified.Fil: Rodríguez Durán, Jessica Jenireth. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Pinto Martinez, Andrea. Instituto de Estudios Avanzados; VenezuelaFil: Castillo, Cecilia. Instituto de Estudios Avanzados; VenezuelaFil: Benaim, Gustavo. Instituto de Estudios Avanzados; Venezuela. Universidad Central de Venezuela. Facultad de Ciencias. Instituto de Biología Experimental; Venezuel

Alergias y el sistema inmune: una revisión desde el aula

Los alérgenos son antígenos que desencadenan una respuesta inmunológica exagerada en personas sensibles, esta respuesta se ve agravada en exposiciones posteriores al mismo antígeno. Existen diversos tipos de alergias, las alergias a inhalantes exteriores como al polen o a hongos; alergias a inhalantes interiores como a los artrópodos, animales, al polvo y al humo; alergia a la ingesta de alimentos y fármacos; alergias por inoculación, ya sea por picadura de insectos o fármacos y por último, alergias por contacto. De acuerdo con la interacción entre el anticuerpo y el antígeno, puede haber cuatro tipos diferentes de hipersensibilidad: Tipo I, II, III y IV; las diferentes reacciones y procesos que ocurren en cada una de ellas dependerán de la exposición al antígeno y la sensibilización del individuo. Una de las respuestas inmunológicas más estudiadas es la hipersensibilidad tipo I, donde se presenta una alergia mediada por los anticuerpos de tipo IgE que se encuentran unidos a la membrana de los mastocitos y basófilos, al unirse con el antígeno, se liberan diversas sustancias las cuales son las responsables de producir las manifestaciones clínicas características como anafilaxis, urticaria, sinusitis, rinitis, tos, estornudos, vómito, entre otros. Los índices de morbilidad por patologías causadas por alergias van en aumento, condiciones ambientales como el cambio climático, polución y procesos psicosociales como el estrés, permiten que las enfermedades por hipersensibilidad inmunológica se consideren relevantes tanto para clínicos como para investigadores de las ciencias básicas, lo que motiva académicamente la realización de esta revisión