title: Benznidazole, the trypanocidal drug used for Chagas disease, induces hepatic NRF2 activation and attenuates the inflammatory response in a murine model of sepsis.
abstract: Molecular mechanisms on sepsis progression are linked to the imbalance between reactive oxygen species (ROS) production and cellular antioxidant capacity. Previous studies demonstrated that benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, has immunomodulatory effects, increasing survival in C57BL/6 mice in a model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). The mechanism by which BZL inhibits inflammatory response in sepsis is poorly understood. Also, our group recently reported that BZL is able to activate the nuclear factor erytroide-derived 2-Like 2 (NRF2) in vitro. The aim of the present work was to delineate the beneficial role of BZL during sepsis, analyzing its effects on the cellular redox status and the possible link to the innate immunity receptor TLR4. Specifically, we analyzed the effect of BZL on Nrf2 regulation and TLR4 expression in liver of mice 24hours post-CLP. BZL was able to induce NRF2 nuclear protein localization in CLP mice. Also, we found that protein kinase C (PKC) is involved in the NRF2 nuclear accumulation and induction of its target genes. In addition, BZL prompted a reduction in hepatic CLP-induced TLR4 protein membrane localization, evidencing its immunomodulatory effects. Together, our results demonstrate that BZL induces hepatic NRF2 activation with the concomitant increase in the antioxidant defenses, and the attenuation of inflammatory response, in part, by inhibiting TLR4 expression in a murine model of sepsis.
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Flavia
authors.initials: F
authors.lastname: Lambertucci
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Omar
authors.initials: O
authors.lastname: Motiño
authors.affiliation: Instituto de Inmunología, Facultad de Ciencias Médicas, UNR, Suipacha 531, 2000 Rosario, Argentina.
authors.forename: Silvina
authors.initials: S
authors.lastname: Villar
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rigalli
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
authors.forename: María
authors.initials: M
authors.lastname: de Luján Alvarez
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Catania
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Cristina Ester
authors.initials: CE
authors.lastname: Carnovale
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Ariel Darío
authors.initials: AD
authors.lastname: Quiroga
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Daniel Eleazar
authors.initials: DE
authors.lastname: Francés
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina. Electronic address: ronco@ifise-conicet.gov.ar.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Ronco
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D014355:Chagas Disease / Q000188:drug therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009593:Nitroimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress; D018805:Sepsis / Q000188:drug therapy*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009593:Nitroimidazoles; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014344:Trypanocidal Agents; C009999:benzonidazole
keywords: Benznidazole; CLP; Liver; NRF2; Sepsis