Effect of Intra-articular 4-(S)-Amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132), a Kinin B2 Receptor Antagonist, on Nociceptive Response in Monosodium Iodoacetate-Induced Experimental Osteoarthritis in Rats

Abstract

The present study was designed to investigate the role of bradykinin (BK) in the knee joint osteoarthritis induced by intraarticular (i.ar.) administration of monosodium iodoacetate (MIA) in the rat, and to determine the efficacy of the kinin B 2 receptor antagonists, 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) and icatibant, in reducing pain. Rats received MIA (1 mg/25 l i.ar.) in the right knee. MEN16132, icatibant (1, 3, and 10 g/25 l i.ar.), or saline were administered 7 days after MIA treatment, and their antinociceptive effect was observed for 2 weeks. MEN16132 induced a marked and sustained reduction of incapacitation produced by MIA, approximately 56% inhibition of pain at 3 g/knee. MEN16132 analgesia was more potent and longer lasting, up to 10 days, than icatibant. MEN16132 (3 g/knee), at different time points from MIA treatment in separate groups of animals, produced comparable maximal antinociceptive effects, whereas the pain response induced by MIA was unaffected if MEN16132 (10 g/knee) was administered in the contralateral knee. Indomethacin at high doses (100 -625 g/knee) inhibited by approximately 40% but with a short duration the MIAinduced pain. MIA treatment produced a significant increase of BK and prostaglandin E 2 (PGE 2 ) metabolite levels in synovial fluid up to 21 days, and PGE 2 metabolite levels were reduced almost to basal values by MEN16132. In conclusion the potent and long-lasting analgesic effect of MEN16132 in MIA-induced osteoarthritis indicates an important role for BK in osteoarthritic pain, and suggests that MEN16132 can be a candidate for the treatment of this chronic disease.Osteoarthritis (OA) is a degenerative joint disease that affects most of the elderly population causing chronic pain and joint disability. In particular, the OA of the knee is characterized by histological changes of the joint involving degeneration of articular cartilage with fibrillation and erosion, synovitis, remodeling of subchondral bone with osteophytes formation at the joint margins, and sclerosis of subchondral bone (Goldring and Goldring, 2007). The pathophysiology behind these modifications is complex and involves a combination of mechanical, cellular, and biochemical processes that are not yet completely understood. Inflammation contributes to increase structural degeneration by releasing catabolic and proinflammatory mediators including cytokines, nitric oxide, and matrix metalloproteinases that may activate chondrocytes and synovial fibroblasts leading to cartilage destruction (Goldenberg et al., 1982;Yasuda, 2006;Sutton et al., 2009). No drug modifying OA progression is currently available, and treatment options are focused on symptomatic relief of pain and inflammation to improve the joint function. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and opiates are widely used, but Article, publication date, and c...

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

“…Longterm bradykinin stimulation of human synoviocytes leads to increased release of IL-6 and IL-8 [21]. Administration of a specific B2 receptor antagonist has been reported to reduce inflammatory pain in rats [22]. These findings support the therapeutic potential of BDKRB2 blockade in OA treatment.…”

Skullcapflavone II inhibits ovalbumin-induced airway inflammation in a mouse model of asthma

“…Bradykinin has been implicated in the pathogenesis of asthma in that elevated kinin levels have been detected in plasma and BAL fluids of asthmatic patients [36,37]. Thus, it was reported that various bradykinin antagonists prevent airway inflammation and antigen-induced hyperresponsiveness [38][39][40]. In addition, TGF-β and VEGF, cytokines are known to be involved in airway remodeling in asthma, were produced in a mouse model of allergic asthma and that the cytokines production was suppressed by the bradykinin antagonist.…”

Osteoarthritis model induced by intra-articular monosodium iodoacetate in rats knee

“…The cartilage -the main target of the degenerative osteoarthritis changes -has two functions: to permit joint motion with minimal friction and to absorb shock preventing bone damage [5][6][7] . At the moment, many palliative drugs as anti-inflammatory, corticosteroids and opioids have been used in the treatment of the disease in humans; however, none of them stopped the evolutionary process of the lesion, which is the main goal of treatment 8 .…”