Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols

PLoS Neglected Tropical Diseases, Jul 2009

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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Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols

et al. (2009) Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols. PLoS Negl Trop Dis 3(7): e477. doi:10.1371/journal.pntd.0000477 Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols Juliana B. R. Corre a Soares 0 1 Diego Menezes 0 1 Marcos A. Vannier-Santos 0 1 Antonio Ferreira-Pereira 0 1 Giulliana T. Almeida 0 1 Thiago M. Venancio 0 1 Sergio Verjovski-Almeida 0 1 Vincent K. Zishiri 0 1 David Kuter 0 1 Roger Hunter 0 1 Timothy J. Egan 0 1 Marcus F. Oliveira 0 1 Malcolm K. Jones, Queensland Institute of Medical Research, Australia 0 Current address: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, MD , United States of America 1 1 Laborato rio de Bioqu mica Redox, Programa de Biologia Molecular e Biotecnologia, Instituto de Bioqu mica Me dica, Universidade Federal do Rio de janeiro , Rio de Janeiro, Brazil, 2 Instituto Gonc alo Moniz, FIOCRUZ, Salvador, Brazil , 3 Departamento de Microbiologia Geral, Instituto de Microbiologia Prof. Paulo de Go es, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil , 4 Departamento de Bioqu mica, Instituto de Qu mica, Universidade de Sa o Paulo , Sa o Paulo , Brazil , 5 Department of Chemistry, University of Cape Town , Rondebosch, Cape Town , South Africa 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. - Funding: This work was supported in part by WHO/TDR, South-South Initiative grant A60265 (MFO-TJE), International Centre for Genetic Engineering and Biotechnology (ICGEB-CRP) grant (CRP/BRA07-03, contract CRP/07/008), CNPq, FAPERJ (MFO through Jovens Cientistas do Nosso Estado 2007) and FAPESP (to SVA). MFO, MAVS and SVA are research scholars from CNPq. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: All authors have read and approved the contents of the manuscript and none of the authors have competing financial interests. There is no significant overlap between the submitted manuscript and any other papers from the same authors under consideration or in press elsewhere. Schistosomiasis is a major parasitic disease that affects 170 million people in sub-Saharan Africa and close to 30 million people in north of Africa, Asia and South America [1]. Recent estimates indicate that 779 million people live in risk areas across 70 countries [2,3,4] raising the possibility that morbidity associated with the disease may be considerably under-estimated [5]. The disease pathology is typically a consequence of an inflammatory granulomatous reaction due to parasite egg deposition in the liver and other host tissues [6]. The major etiological agent of human schistosomiasis is the platyhelmith Schistosoma mansoni which is known to digest large amounts of blood in order to complete i (...truncated)


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Juliana B. R. Corrêa Soares, Diego Menezes, Marcos A. Vannier-Santos, Antonio Ferreira-Pereira, Giulliana T. Almeida, Thiago M. Venancio, Sergio Verjovski-Almeida, Vincent K. Zishiri, David Kuter, Roger Hunter, Timothy J. Egan, Marcus F. Oliveira. Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols, PLoS Neglected Tropical Diseases, 2009, 7, DOI: 10.1371/journal.pntd.0000477