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INTERFERENCE WITH HEMOZOIN FORMATION REPRESENTS AN IMPORTANT MECHANISM OF SCHISTOSOMICIDAL ACTION OF ANTIMALARIAL QUINOLINE METHANOLS
Autor
Afiliación
Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Laborato´rio de Bioquı´mica Redox, Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Prof. Paulo de Goes. 3 Departamento de Microbiologia Geral. Rio de Janeiro, RJ, Brasil
Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil
Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil
Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Laborato´rio de Bioquı´mica Redox, Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Prof. Paulo de Goes. 3 Departamento de Microbiologia Geral. Rio de Janeiro, RJ, Brasil
Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil
Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil
Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
University of Cape Town. Department of Chemistry. Rondebosch, Cape Town, South Africa
Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Laborato´rio de Bioquı´mica Redox, Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil
Resumen en ingles
Background: The parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis,
which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and
reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group
has demonstrated that heme crystallization into hemozoin (Hz) within the S. mansoni gut is a major heme detoxification route
with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we
investigated the effects of three antimalarial compounds, quinine (QN), quinidine (QND) and quinacrine (QCR) in a murine
schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches.
Methodology/Principal Findings: Treatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections
of QN, and QND (75 mg/kg/day) from the 11th to 17th day after infection caused significant decreases in worm burden
(39%–61%) and egg production (42%–98%). Hz formation was significantly inhibited (40%–65%) in female worms recovered
from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN
treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and
reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated
that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms.
Conclusions: The overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols
indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action
of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat
schistosomiasis.
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