title: Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis.
abstract: Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. A few studies have shown that TQ exhibits anti-inflammatory activities in experimental models of rheumatoid arthritis (RA) through mechanisms that are not fully understood. The aim of this work was to evaluate the in vitro and in vivo effects of TQ and to investigate its influence on the major signalling pathways involved in pathophysiological RA changes. We used isolated human RA fibroblast-like synoviocytes (FLS) and a rat adjuvant-induced arthritis model of RA. In isolated RA FLS, TQ (0-10 µM) was not cytotoxic and inhibited slightly lipopolysaccharide (LPS)-induced FLS proliferation and strongly H(2)O(2)-induced 4-hydroxynonenal (HNE) generation. By studying different inflammatory and catabolic factors, we determined that TQ significantly abolished LPS-induced interleukin-1beta (IL-1β), tumour necrosis factor-alpha (TNFα), metalloproteinase-13, cyclooxygenase-2, and prostaglandin E(2). Furthermore, LPS-induced the phosphorylation of p38 mitogen-activated protein kinase, extracellular-regulated kinases ½, and nuclear factor-kappaB-p65 were also blocked by TQ in time-dependent manner. In our experimental RA model, the oral administration of TQ 5 mg/kg/day significantly reduced the serum levels of HNE, IL-1β and TNFα as well as bone turnover markers, such as alkaline phosphatase and tartrate-resistant acid phosphatase. The protective effects of TQ against RA were also evident from the decrease in arthritis scoring and bone resorption. In conclusion, the fact that TQ abolishes a number of factors known to be involved in RA pathogenesis renders it a clinically valuable agent in the prevention of articular diseases, including RA.
authors.affiliation: Department of Surgery, University of Montreal, Montreal, Quebec, Canada.
authors.forename: France
authors.initials: F
authors.lastname: Vaillancourt
authors.forename: Patrick
authors.initials: P
authors.lastname: Silva
authors.forename: Qin
authors.initials: Q
authors.lastname: Shi
authors.forename: Hassan
authors.initials: H
authors.lastname: Fahmi
authors.forename: Julio C
authors.initials: JC
authors.lastname: Fernandes
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benderdour
mesh_terms: D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013582:Synovial Fluid / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C003466:thymoquinone