The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells.
Bottom Line: We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro.GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro.In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA.
Affiliation: Pharmaceutical Science Research Division, King's College London, London, England.Show MeSH
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Mentions: GYY4137 (50 mg/kg, i.p.) or saline was administered to mice either 1 hr before or 6 or 18 hrs after intra-articular injection of CFA. In all cases, animals were killed 24 hrs after CFA injection. Saline did not cause knee joint swelling at any time-point of injection (data not shown). Pre-treatment (1 hr) of animals with GYY4137 resulted in a significant increase in CFA-induced knee joint swelling (Fig. 6A) without any change in synovial fluid MPO activity (Fig. 6B). In contrast, injection of GYY4137 18 hrs after CFA reduced knee joint swelling (Fig. 6C) and also decreased synovial fluid MPO activity (Fig. 6D). Administration of GYY4137 6 hrs after intra-articular injection of CFA did not affect knee joint diameter (Fig. 7A), but did significantly reduce synovial fluid MPO activity (Fig. 7B) and NAG (Fig. 7C), TNF-α (Fig. 7D), IL-1β (Fig. 7E), IL-6 (Fig. 7F) and IL-8 (Fig. 7G) concentrations. Intriguingly, despite the apparent inability of GYY4137 administered 6 hrs after CFA injection to affect knee joint swelling, evidence of reduced neutrophil infiltration and inflammation was also apparent upon histological examination of treated knee joints (Fig. 8).
Affiliation: Pharmaceutical Science Research Division, King's College London, London, England.