Dopaminergic antagonists inhibit bile chemotaxis of adult Clonorchis sinensis and its egg production

Abstract

Human clonorchiasis, caused by Clonorchis sinensis, is endemic in East Asian countries. C. sinensis metacercariae excyst in the duodenum of mammalian hosts, migrate to the intrahepatic bile duct, and mature into adults in the milieu of bile. We have previously shown that newly excysted juvenile C. sinensis move chemotactically toward bile and bile acids. Here, the chemotactic behavior of adult C. sinensis (CsAd) toward bile and bile acids was investigated. CsAds moved toward 0.05-5% bile and were most attracted to 0.5% bile but moved away from 10% bile. Upon exposure to 1-10% bile, CsAds eventually stopped moving and then died quickly. Among bile acids, CsAds showed strong chemotaxis toward cholic acid (CA) and deoxycholic acid. On the contrary, CsAds repelled from lithocholic acid (LCA). Moreover, at higher than 10 mM LCA, CsAds became sluggish and eventually died. Dopamine D-1 receptor antagonists (LE-300 and SKF-83566), D-2/3 receptor antagonists (raclopride and its derivative CS-49612), and a dopamine re-uptake inhibitor inhibited CA-induced chemotaxis of CsAds almost completely. Clinically used antipsychotic drugs, namely chlorpromazine, haloperidol, and clozapine, are dopaminergic antagonists and are secreted into bile. They completely inhibited chemotaxis of CsAds toward CA. At the maximum doses used to treat patients, the three tested medicines only expelled 2-12% of CsAds from the experimentally infected rabbits, but reduced egg production by 64-79%. Thus, antipsychotic medicines with dopaminergic antagonism could be considered as new anthelmintic candidates for human C. sinensis infections. Author summary The liver fluke, Clonorchis sinensis, is endemic in East Asian countries. People get infected through consumption of raw freshwater fish carrying C. sinensis metacercaria, an infective form to human. The metacercaria excysts in the human duodenum and the juvenile fluke migrates into the intrahepatic bile duct following chemical cues provided by bile. The juvenile fluke matures in the intrahepatic bile duct, and the adult fluke causes inflammatory injuries to the bile duct, which can eventually lead to bile duct cancer. Bile plays a critical role in the fluke's life in the human host. In this study, we demonstrated that the adult C. sinensis fluke was attracted by bile and bile acids, such as cholic acid and deoxycholic acid, but repelled by lithocholic acid. The chemotactic attraction of the fluke to cholic acid was suppressed by experimental dopaminergic antagonists. Clinically used antipsychotic drugs that are dopaminergic antagonists, namely chlorpromazine, haloperidol, and clozapine, also strongly suppressed the chemotaxis. While the drugs elicited a minor response of fluke expulsion from the bile ducts of infected rabbits, they significantly reduced egg production. The results could be utilized to develop effective drugs to treat C. sinensis infection.