Interference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols.
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.


RESULTS
Treatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day) from the 11(th) to 17(th) 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.
Corrêa Soares
Juliana B R
JB
Laboratório de Bioquímica Redox, Programa de Biologia Molecular e Biotecnologia, Instituto de Bioquímica Médica, Universidade Federal do Rio de janeiro, Rio de Janeiro, Brazil.
Menezes
Diego
D
Vannier-Santos
Marcos A
MA
Ferreira-Pereira
Antonio
A
Almeida
Giulliana T
GT
Venancio
Thiago M
TM
Verjovski-Almeida
Sergio
S
Zishiri
Vincent K
VK
Kuter
David
D
Hunter
Roger
R
Egan
Timothy J
TJ
Oliveira
Marcus F
MF
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D005260:Female; D041981:Gastrointestinal Tract / Q000469:parasitology; D020869:Gene Expression Profiling; D006420:Hemeproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000648:ultrastructure; D008099:Liver / Q000469:parasitology; D008297:Male; D051379:Mice; D010270:Parasite Egg Count; D011796:Quinacrine / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000648:ultrastructure; D012555:Schistosomiasis mansoni / Q000188:drug therapy
D000871:Anthelmintics; D006420:Hemeproteins; C020753:hemozoin; D011803:Quinine; D011796:Quinacrine; D011802:Quinidine