Immunopharmacology and InflammationEvidence for the complementary and synergistic effects of the three-alkaloid combination regimen containing berberine, hypaconitine and skimmianine on the ulcerative colitis rats induced by trinitrobenzene-sulfonic acid

Ulcerative colitis involves complicated etiology and presents diverse symptoms including intestine inflammation, bowel pain and diarrhea. Anti-inflammatory drugs are the mainstay in patient care, accompanied with antidiarrhea and analgesic agents used as symptomatic treatment. A classic traditional Chinese medicine formula, Fructus Mume pill (FMP), showed remarkable therapeutic efficacy in treating ulcerative colitis. However, since it contains many herbs and countless chemicals, the underlying mechanism is not clear. In this study, we selected three alkaloids from FMP, namely, berberine, hypaconitine and skimmianine to study the individual drug effect and compare these results with the BHS combination on: 1) The recovery of ulcerative colitis rats induced by trinitrobenzene-sulfonic acid. 2) Mice with xylene-induced acute exudative edema and acetic acid-induced writhing. 3) Gastrointestinal transit inhibition, and 4) the response of HT29 cells after treatment with lipopolysaccharide. We found that the compound hypaconitine showed a potent analgesic effect, while skimmianine acted as an antidiarrhea agent and the component berberine was the key agent exerting anti-inflammatory effect. However, since berberine killed the commensal bacteria and induced lipopolysaccharide release, it could at the same time aggravate colon inflammation. The three-alkaloid combination BHS produced complementary and synergistic effects in colon inflammation recovery, relieving acetic acid-induced bowel pain and xylene-induced acute exudative edema. BHS also decreased lipopolysaccharide production and enhanced the therapeutic efficacy. It is hoped that this study will lay the foundation to further dissect and understand the FMP formula to improve the treatment with simplified and well defined drug combinations for this dreadful disease.