title: 7-hydroxyfrullanolide, a sesquiterpene lactone, inhibits pro-inflammatory cytokine production from immune cells and is orally efficacious in animal models of inflammation.
abstract: A promising therapeutic approach to reduce pathological inflammation is to inhibit the increased production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6). In this study, we investigated the anti-inflammatory potential of 7-hydroxyfrullanolide (7HF). 7HF is an orally bioavailable, small molecule sesquiterpene lactone isolated from the fruit of Sphaeranthus indicus. 7HF significantly and dose-dependently diminished induced and spontaneous production of TNF-alpha and IL-6 from freshly isolated human mononuclear cells, synovial tissue cells isolated from patients with active rheumatoid arthritis and BALB/c mice. Oral administration of 7HF significantly protected C57BL/6J mice against endotoxin-mediated lethality. In the dextran sulfate sodium (DSS) model of murine colitis, oral administration of 7HF prevented DSS-induced weight loss, attenuated rectal bleeding, improved disease activity index and diminished shortening of the colon of C57BL/6J mice. Histological analyses of colonic tissues revealed that 7HF attenuated DSS-induced colonic edema, leukocyte infiltration in the colonic mucosa and afforded significant protection against DSS-induced crypt damage. 7HF was also significantly efficacious in attenuating carrageenan-induced paw edema in Wistar rats after oral administration. In the collagen-induced arthritis in DBA/1J mice, 7HF significantly reduced disease associated increases in articular index and paw thickness, protected against bone erosion and joint space narrowing and prominently diminished joint destruction, hyperproliferative pannus formation and infiltration of inflammatory cells. Collectively, these results provide evidence that 7HF-mediated inhibition of pro-inflammatory cytokines functionally results in marked protection in experimental models of acute and chronic inflammation.
authors.affiliation: The Department of Pharmacology, Piramal Life Sciences Limited, Mumbai-400063, Maharashtra, India. lyle.fonseca@piramal.com
authors.forename: Lyle C
authors.initials: LC
authors.lastname: Fonseca
authors.forename: Shruta S
authors.initials: SS
authors.lastname: Dadarkar
authors.forename: Aurelio S
authors.initials: AS
authors.lastname: Lobo
authors.forename: Ashish C
authors.initials: AC
authors.lastname: Suthar
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Chauhan
authors.forename: Shanthi
authors.initials: S
authors.lastname: Chandrababu
authors.forename: Somesh D
authors.initials: SD
authors.lastname: Sharma
authors.forename: Nilesh M
authors.initials: NM
authors.lastname: Dagia
authors.forename: Muralidhara
authors.initials: M
authors.lastname: Padigaru
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology; D019659:Asteraceae / Q000737:chemistry*; D003092:Colitis / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: C553906:7-hydroxyfrullanolide; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha