title: Intestinal interleukin-10 mobilization as a contributor to the anti-arthritis effect of orally administered madecassoside: a unique action mode of saponin compounds with poor bioavailability.
abstract: Madecassoside, a triterpenoid saponin present in Centella asiatica herbs with extremely low bioavailability, possesses excellent anti-rheumatoid arthritis property after oral administration. Such a disconnection between poor pharmacokinetic property and undoubted bioactivity also exists in many other herbal medicines. However, there is no reasonable explanation for this phenomenon to date. Here we showed that orally administered madecassoside displayed marked therapeutic effect on collagen-induced arthritis (CIA) in rats, which was accompanied by a systemic downregulation of inflammatory cytokines and an upregulation of anti-inflammatory cytokine IL-10. In vitro assays demonstrated that neither madecassoside nor its main metabolite madecassic acid could directly interfere with the secretion of inflammatory cytokines and IL-10. Intraperitoneal injection of madecassoside or madecassic acid was absent of significant effects on CIA progression, which further excluded the possibility of systemic action and highlighted the indispensable role of intestinal tracts. Notably, madecassoside could dramatically enhance the secretion of IL-10 from the small intestine of CIA rats probably through increasing the number of Foxp3(+) T lymphocytes in the lamina propria. In conclusion, madecassoside displays anti-arthritis property not by absorption into blood or by its metabolite, but through an intestine-dependent manner. The action can be mediated by, at least partially, the mobilization of IL-10 that originates from small intestines.
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Yannong
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Leng
authors.affiliation: Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Kong
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: yuedaicpu@hotmail.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: yfxiacpu@126.com.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D028041:Centella; D005260:Female; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000819:agonists / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D010936:Plant Extracts; D051381:Rats; D017208:Rats, Wistar; D012503:Saponins / Q000493:pharmacokinetics* / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; C526146:Centella asiatica extract; D010936:Plant Extracts; D012503:Saponins; D014315:Triterpenes; D016753:Interleukin-10; C093443:madecassoside; C001669:madecassic acid
keywords: Interleukin-10; Madecassoside; Pharmacokinetics–pharmacodynamics discrepancy; Rheumatoid arthritis; Small intestine