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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01181

Plumbagin prevents secretory diarrhea by inhibiting CaCC and CFTR channel activities

 Bo Yu1*,  Xiaojuan Zhu1, Xinyu Yang1, Lingling Jin2, Jia Xu1,  Tonghui Ma1, 2, 3 and  Hong Yang1
  • 1School of Life Sciences, Liaoning Normal University, China
  • 2College of Basic Medical Sciences, Dalian Medical University, China
  • 3Nanjing University of Chinese Medicine, China

Secretory diarrhea, which primarily originates through intestinal pathogens and viruses, is a health burden in many regions worldwide. Enterocyte Cl− channels, as the final step in enterotoxin-induced fluid secretion, constitute an attractive class of targets for diarrhea therapy. Chloride channel inhibitors have become a new class of candidates for anti-secretion and anti-intestinal motility agents. In the present study, we identified plumbagin as a TMEM16A inhibitor in a cell-based fluorescence-quenching assay, the IC50 value was ~12.46 μM. Short-circuit current measurements showed that plumbagin reversibly inhibited the Eact-induced Cl− current on the apical side of TMEM16A-transfected FRT cells with no significant effect on cytoplasmic Ca2+ signaling. Notably, plumbagin also inhibited the activity of intestinal epithelial calcium-activated chloride channel (CaCC) and cystic fibrosis transmembrane conductance regulator (CFTR) in both HT-29 cells and mouse colons, but had no effects on the activity of the Na+-K+ ATPase or K+ channels. In in-vivo experiments, the administration of plumbagin reduced both Escherichia coli heat-stable enterotoxin (STa)- and cholera toxin (CT)-induced intestinal fluid secretion. In neonatal mouse models of cholera toxin- and rotavirus infection-induced diarrhea, 0.4 μg plumbagin inhibited secretory diarrhea by >40% and 50%, respectively, without affecting intestinal epithelial integrity or the rotaviral infection. In addition, plumbagin exerted inhibitory effects on the vasoactive intestinal peptide (VIP)-, prostaglandin E2 (PGE2)- and 5-hydroxytryptamine (5-HT)-stimulated Cl− currents. In the evaluations of intestinal motility, plumbagin significantly delayed intestinal motility and inhibited intestinal smooth muscle contractility without an evident impact on contractive frequency. Collectively, our results indicate that plumbagin inhibits both Ca2+- and cAMP-activated Cl− channels, accounting for the mechanisms of plumbagin inhibition of chloride secretion and intestinal motility. Thus, plumbagin can be a lead compound in the treatment of cholera toxin-induced, Traveler’s and rotaviral diarrhea as well as other types of secretory diarrhea that result from excessive intestinal fluid secretion and increased intestinal peristalsis.

Keywords: Plumbagin, Secretory diarrhea, Cystic Fibrosis Transmembrane Conductance Regulator, Calcium-activated chloride channel, intestinal motility

Received: 16 Apr 2019; Accepted: 13 Sep 2019.

Copyright: © 2019 Yu, Zhu, Yang, Jin, Xu, Ma and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Bo Yu, School of Life Sciences, Liaoning Normal University, Dalian, 110036, Liaoning Province, China,