Sesquiterpene lactones improve secretory diarrhea symptoms by inhibiting intestinal Ca2+-activated Cl– channel activities directly and indirectly

Secretory diarrhea caused by bacteria and viruses is usually accompanied by activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated Cl- channels (CaCCs) in the intestinal epithelium. Inhibition of CFTR and CaCCs activities significantly reduces fluid losses and intestinal motility in diarrheal diseases. For this reason, CFTR and CaCCs are potential targets of therapeutic drug screening. Here, we reported that the sesquiterpene lactones, alantolactone (AL) and isoalantolactone (iAL), significantly inhibited ATP and Eact-induced short-circuit currents in T84, HT-29 and Fischer rat thyroid (FRT) cells expressing transmembrane protein 16A (TMEM16A) in a concentration-dependent manner. AL and iAL also inhibited the CaCC-mediated short-circuit currents induced by carbachol in the mouse colons. Both compounds inhibited forskolin-induced currents in T84 cells but did not significantly affect mouse colons. In vivo studies indicated that AL and iAL attenuated gastrointestinal motility and decreased watery diarrhea in rotavirus-infected neonatal mice. Preliminary mechanism studies showed that AL and iAL inhibited CaCCs at least partially by inhibiting Ca2+ release and basolateral membrane K+ channels activity. These findings suggest a new pharmacological activity of sesquiterpene lactone compounds that might lead to the development of treatments for rotaviral secretory diarrhea.