title: Oral administration of the NADPH-oxidase inhibitor apocynin partially restores diminished cartilage proteoglycan synthesis and reduces inflammation in mice.
abstract: Apocynin, an inhibitor of NADPH-oxidase, is known to partially reverse the inflammation-mediated cartilage proteoglycan synthesis in chondrocytes. More recently, it was reported that apocynin prevents cyclooxygenase (COX)-2 expression in monocytes. The present study aimed to investigate whether these in vitro features of apocynin could be confirmed in vivo. In a mouse model of zymosan-induced acute arthritis apocynin was administered orally (0, 3.2, 16 and 80 microg/ml in the drinking water) and the effects on cartilage proteoglycan synthesis were monitored. In a mouse model of zymosan-induced inflammation of the ears apocynin was administered orally (14 mg/kg/day by gavage) and the effects on ear swelling and ex vivo produced prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-stimulated blood cells were measured. In this study, ibuprofen was used as a positive control (50 mg/kg/day by gavage) and animals received vehicle as a negative control. Apocynin dose-dependently reversed the inhibition of proteoglycan synthesis in articular cartilage of the arthritic joint. A statistically significant increase in proteoglycan synthesis was found at a dose of 80 microg/ml apocynin. Apocynin did not affect the proteoglycan synthesis of the control knee joints. Apocynin significantly decreased the zymosan-induced ear swelling at 1, 2 and 4 h (hours) after zymosan injection versus the vehicle treated group at 14 mg/kg/day. The ex vivo production of PGE2 by LPS-stimulated blood cells was significantly decreased after in vivo apocynin treatment. Ibuprofen decreased ear swelling at the same time-points as apocynin and inhibited the ex vivo produced PGE2. In conclusion, the present study confirmed two important features of apocynin in vivo: (1) oral administration of apocynin can partially reverse the inflammation-induced inhibition of cartilage proteoglycan synthesis, and (2) oral administration of apocynin has COX inhibitory effects similar to the non-steroidal anti-inflammatory drug (NSAID) ibuprofen. Therefore, apocynin might be of potential use during the treatment of chronic inflammatory joint diseases like osteoarthritis or rheumatoid arthritis.
authors.affiliation: Numico Research P.O. Box 7005, Wageningen, NL-6700 CA Wageningen, The Netherlands. Sander.Hougee@Numico-Research.nl
authors.forename: Sander
authors.initials: S
authors.lastname: Hougee
authors.forename: Anita
authors.initials: A
authors.lastname: Hartog
authors.forename: Annemarie
authors.initials: A
authors.lastname: Sanders
authors.forename: Yvo M F
authors.initials: YM
authors.lastname: Graus
authors.forename: Maarten A
authors.initials: MA
authors.lastname: Hoijer
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Henk M
authors.initials: HM
authors.lastname: van Beuningen
authors.forename: H Friso
authors.initials: HF
authors.lastname: Smit
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis; D004326:Drinking; D004427:Ear Diseases / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D011509:Proteoglycans / Q000096:biosynthesis*; D015054:Zymosan
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011509:Proteoglycans; D015054:Zymosan; C056165:acetovanillone; D019255:NADPH Oxidases; D015232:Dinoprostone