title: Nitric oxide-releasing indomethacin enhances susceptibility to Trypanosoma cruzi infection acting in the cell invasion and oxidative stress associated with anemia.
abstract: Trypanosoma cruzi is the causative agent of Chagas disease. Approximately 8 million people are thought to be affected with this disease worldwide. T. cruzi infection causes an intense inflammatory response, which is critical for the control of parasite proliferation and disease development. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as chemopreventive agents. In this study, we investigated the effect of NO-indomethacin on parasite burden, cell invasion, and oxidative stress in erythrocytes during the acute phase of infection. NO-indomethacin was dissolved in dimethyl formamide followed by i.p. administration of 50 ppm into mice 30 min after infection with 5×10(3) blood trypomastigote forms (Y strain). The drug was administered every day until the animals died. Control animals received 100 μL of drug vehicle via the same route. Within the NO-indomethacin-treatment group, parasitemia and mortality (100%) were higher and oxidative stress in erythrocytes, anemia, and entry of parasites into macrophages were significantly greater than that seen in controls. Increase in the entry and survival of intracellular T. cruzi was associated with inhibition of nitric oxide production by macrophages treated with NO-indomethacin (2.5 μM). The results of this study provide strong evidence that NO-NSAIDs potently inhibit nitric oxide production, suggesting that NO-NSAID-based therapies against infections would be difficult to design and would require caution.
authors.affiliation: Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970 Londrina, Paraná, Brazil.
authors.forename: Vera Lucia Hideko
authors.initials: VL
authors.lastname: Tatakihara
authors.affiliation: Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970 Londrina, Paraná, Brazil.
authors.forename: Aparecida Donizette
authors.initials: AD
authors.lastname: Malvezi
authors.affiliation: Centro de Ciências Sociais Aplicadas, Universidade Estadual do Oeste do Paraná - UNIOESTE, Francisco Beltrão 85.605-010, Paraná, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Panis
authors.affiliation: Laboratório de Fisiopatologia e Radicais Livres, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970 Londrina, Paraná, Brazil.
authors.forename: Rubens
authors.initials: R
authors.lastname: Cecchini
authors.affiliation: Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970 Londrina, Paraná, Brazil.
authors.forename: Nagela Ghabdan
authors.initials: NG
authors.lastname: Zanluqui
authors.affiliation: Laboratório de Biologia Molecular de Microrganismos, Departamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná 86051-970, Brazil.
authors.forename: Lucy Megumi
authors.initials: LM
authors.lastname: Yamauchi
authors.affiliation: Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970 Londrina, Paraná, Brazil.
authors.forename: Maria Isabel Lovo
authors.initials: MI
authors.lastname: Martins
authors.affiliation: Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970 Londrina, Paraná, Brazil.
authors.forename: Rosiane Valeriano
authors.initials: RV
authors.lastname: da Silva
authors.affiliation: Laboratório de Biologia Molecular de Microrganismos, Departamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná 86051-970, Brazil.
authors.forename: Sueli Fumie
authors.initials: SF
authors.lastname: Yamada-Ogatta
authors.affiliation: Hospital Israelita Albert Einstein, Av. Albert Einstein 627-701, 2-SS Bloco A, 05651-901 São Paulo, Brazil; Instituto de Investigação em Imunologia, Instituto Nacional de Ciência e Tecnologia (INCT), Brazil.
authors.forename: Luiz Vicente
authors.initials: LV
authors.lastname: Rizzo
authors.affiliation: Laboratório de Fisiologia e Fisiopatologia Cardiovascular, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná 86051-970, Brazil.
authors.forename: Marli Cardoso
authors.initials: MC
authors.lastname: Martins-Pinge
authors.affiliation: Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970 Londrina, Paraná, Brazil. Electronic address: pingefilho@uel.br.
authors.forename: Phileno
authors.initials: P
authors.lastname: Pinge-Filho
mesh_terms: D000740:Anemia / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000737:chemistry / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D018512:Parasitemia / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D014349:Trypanosoma cruzi / Q000472:pathogenicity*
chemical_list: C000596777:N-acetylcysteine-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 4-(nitrooxy)butyl ester; D009566:Nitrates; D009569:Nitric Oxide; D007213:Indomethacin
keywords: Cell invasion; Macrophages; NO-indomethacin; Nitric oxide; Oxidative stress; Trypanosoma cruzi