title: Nonsteroidal anti-inflammatory drugs (NSAID) sparing effects of glucosamine hydrochloride through N-glycosylation inhibition; strategy to rescue stomach from NSAID damage.
abstract: Gastrointestinal or cardiovascular complications limit nonsteroidal anti-inflammatory drugs (NSAID) prescription. Glucosamine hydrochloride (GS-HCl) alternatively chosen, but debates still exist in its clinical efficiency. COX-2 instability through inhibiting COX-2 N-glycosylation of GS-HCl raised the possibility of NSAID sparing effect. Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect. IEC-6 cells were stimulated with TNF-α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS-HCl by Western blotting and RT-PCR. C57BL/6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS-HCl after 3 weeks. TNF-α increased the expression of COX-2, iNOS and inflammatory cytokines, but GS-HCl significantly attenuated TNF-α-induced COX-2 expression. Decreased COX-2 after GS-HCl was caused by N-glycosylation inhibition as much as tunicamycin. Combination of reduced dose of indomethacin and GS-HCl significantly reduced the expressions of ICAM-1, VCAM-1, IL-8, IL-1β, MMP-2, MMP-7, MMP-9, and MMP-11 mRNA as well as NF-κB activation better than high dose indomethacin alone. These NSAID sparing effect of GS-HCl was further proven in collagen-induced arthritis model. Combination of GS-HCl and 2.5 mg/kg indomethacin showed significant protection from gastric damages as well as efficacious anti-arthritic effect. Taken together, COX-2 N-glycosylation inhibition by GS-HCl led to indomethacin sparing effects, based on which combination of GS-HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID-induced gastric damage as well as excellent anti-arthritic effects.
authors.affiliation: CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.forename: H
authors.initials: H
authors.lastname: Hong
authors.forename: Y M
authors.initials: YM
authors.lastname: Han
authors.forename: N
authors.initials: N
authors.lastname: Kangwan
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.forename: E H
authors.initials: EH
authors.lastname: Kim
authors.forename: K B
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005944:Glucosamine / Q000008:administration & dosage*; D006031:Glycosylation; D007213:Indomethacin / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases; D005944:Glucosamine; D007213:Indomethacin