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

PLoS Negl Trop Dis. 2020 Mar 30;14(3):e0008220. doi: 10.1371/journal.pntd.0008220. eCollection 2020 Mar.

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 D1 receptor antagonists (LE-300 and SKF-83566), D2/3 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthelmintics / administration & dosage
  • Anthelmintics / pharmacology*
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / pharmacology*
  • Bile / metabolism
  • Chemotactic Factors / metabolism
  • Chemotaxis / drug effects*
  • Cholic Acid / metabolism
  • Clonorchiasis / drug therapy
  • Clonorchis sinensis / drug effects*
  • Clonorchis sinensis / physiology*
  • Disease Models, Animal
  • Dopamine Antagonists / administration & dosage
  • Dopamine Antagonists / pharmacology*
  • Female
  • Fertility / drug effects
  • Humans
  • Lithocholic Acid / metabolism
  • Rabbits
  • Survival Analysis
  • Treatment Outcome

Substances

  • Anthelmintics
  • Antipsychotic Agents
  • Chemotactic Factors
  • Dopamine Antagonists
  • Lithocholic Acid
  • Cholic Acid

Grants and funding

This research was supported by the Korea National Institute of Health, Ministry of Health and Welfare, Korea (grant number 2013-E54006-00 and 2014-E54005-00) to SJH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.