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.

Clonorchis sinensis infection induces hepatobiliary injury via disturbing sphingolipid metabolism and activating sphingosine 1-phosphate receptor 2

“…The preparation refers to the previously described ( Yu et al., 2016 ; Dai et al., 2020 ). Briefly, Pseudorasbora parva (a kind of freshwater fish) obtain from endemic areas of C. sinensis infection, and screen out the positive fish after morphological identification.…”

Dopamine, Immunity, and Disease

“…In addition to driving immune cell chemotaxis, dopamine can also influence inflammation and immune activity by modulating the movement of bacteria and pathogens. Antagonizing D1- and D2-like receptors blocked liver fluke ( Clonorchis sinensis ) larva chemotaxis into the bile duct, indicating that dopamine plays a role in the development of clonorchiasis ( Dai et al, 2020 ). High levels of dopamine (5 × 10 −5 M) also increased the expression of flagellar motility-related genes and the swimming motility of the aquatic bacterium Vibrio harveyi , a Gram-negative bacterium that is a major pathogen of all aquatic organisms.…”

Comparative analysis of bile metabolic profile in patients with biliary obstruction complicated by Clonorchis sinensis infection

“…Therefore, it is of great significance to distinguish between patients of biliary obstruction (OB) and biliary obstruction with C. sinensis infection (OB+C.s). Adult C. sinensis parasitize in mammals’ bile ducts, where they are exposed to bile all their entire lives ( Dai et al., 2020 ). We assumed that adult C. sinensis continuously interact with bile components.…”