morphinans and Osteoarthritis

Morphine and its derivatives play inevitably important role in the μ-opioid receptor (MOR) targeted antinociception. A structure-activity relationship study is presented for novel and known orvinol and thevinol derivatives with varying 3-O, 6-O, 17-N and 20-alkyl substitutions starting from agonists, antagonists and partial agonists. In vitro competition binding experiments with [

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Inflammation; Male; Molecular Docking Simulation; Molecular Structure; Morphinans; Osteoarthritis; Rats, Wistar; Receptors, Opioid, mu; Structure-Activity Relationship

Pathological changes, such as articular cartilage degeneration, destruction, and hyperosteogeny, are regarded as the main features of osteoarthritis (OA). Sinomenine (SIN) is a monomeric component purified from the plant Sinomenium acutum which has been found to have anti-inflammatory effects, however, the mechanism of action of SIN on OA is not clear. In this study, we evaluated whether SIN could regulate the inflammatory response induced by interleukin (IL)-1β and improve outcomes in the instability model of OA (medial meniscus mice (DMM)) by acting on the Nrf2/HO-1 and NF-κ B signaling pathways in chondrocytes. From our experiments, which include Griess reaction, ELISA, Western blot, and immunofluorescence, we found that SIN not only down-regulated the expression of pro-inflammatory factors induced by IL-1β, including; inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitricoxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), but also decreased the production of IL-1β-induced cartilage matrix catabolic enzymes including; ADAMTS-5 and MMPs, in mouse chondrocytes. In addition, the degradation of aggrecan and type II collagen protein in the extracellular matrix (ECM) stimulated by IL-1β was reversed. Most importantly, we have revealed for the first time that in OA, SIN inhibited the inflammatory response and ECM degradation by activating the Nrf2/HO-1 signaling pathways and inhibiting NF-κB activity in mouse-cartilage cells. In in vivo experiments, SIN treatment helped to improve the cartilage destruction in OA model mice. In conclusion, this study has demonstrated that SIN inhibits the IL-1β-induced inflammatory response and cartilage destruction by activating the Nrf2/HO-1 signaling pathway and inhibiting the NF-κB signaling pathway in mouse chondrocytes, suggesting a new use for SIN in the treatment of OA.

Topics: Animals; Anti-Inflammatory Agents; Cartilage, Articular; Cells, Cultured; Chondrocytes; Heme Oxygenase-1; Knee Joint; Male; Membrane Proteins; Mice, Inbred C57BL; Morphinans; NF-E2-Related Factor 2; NF-kappa B; Osteoarthritis; Signal Transduction

While intra-articular injection of sinomenine hydrochloride has a therapeutic effect on osteoarthritis, it has a short half-life, and is thermolabile and photolabile. The aim of this research was to evaluate the sustained-release of sinomenine hydrochloride from an injectable sinomenine hydrochloride and sodium hyaluronate compound (CSSSI) and its therapeutic effect in a rabbit model of osteoarthritis following intra-articular injection.. An injectable compound consisting of 1% sodium hyaluronate and 2.5% sinomenine hydrochloride was prepared and kept as the experiment group, and 2.5% sinomenine hydrochloride was prepared and kept as the control group. The cumulative mass release was measured at different time points in each group in vitro. Sixty-five male Zelanian rabbits were randomly divided into five groups: 15 (30 knees) each for the control, sodium hyaluronate, sinomenine hydrochloride, and CSSSI groups respectively, and five (10 knees) for the modeling group. Papain was injected into both knees of each rabbit for model establishment. Subsequently, 0.2 ml of the corresponding drugs was injected into the articular cavities of the remaining experiment groups, while the control group was treated with 0.2 ml normal saline. All groups were treated once a week for 4 weeks. Seven days after the last treatment, knees were anatomized to perform pathological observations and Mankin's evaluation of the synovium. Four groups were compared using the SPSS 13.0 software package.. In the in vitro sustained-release experiments, 90% of the drug was released in the experiment group 360 minutes following the injection. Comparison of the Mankin's evaluations of the four groups illustrated statistical discrepancies (P < 0.05). In further paired comparisons of the CSSSI group vs. modeling control/sodium hyaluronate/sinomenine hydrochloride groups, statistical significance was uniformly obtained. Moreover, sodium hyaluronate and sinomenine hydrochloride treatments showed significant improvement over the modeling control (P < 0.05), whereas sodium hyaluronate vs. sinomenine hydrochloride comparison failed to reach significance (P > 0.05).. CSSSI has a sustained-release effect on sinomenine hydrochloride. Intra-articular injection of CSSSI was significantly better than the sole sodium hyaluronate or sinomenine hydrochloride for the treatment of osteoarthritis in a rabbit model.

Topics: Animals; Hyaluronic Acid; Injections, Intra-Articular; Male; Morphinans; Osteoarthritis; Rabbits; Random Allocation

Sinomenine (SIN), an alkaloid extracted from the stem of the Chinese medicinal plant sinomenium acutum, has been used for treating rheumatoid arthritis. But little is known whether SIN has a protective effect on osteoarthritis (OA). In this study, we investigated the protective effect of SIN on IL-1beta-induced proteoglycan degradation and apoptosis in rabbit articular cartilage and chondrocytes. Treatment with 10 ng/ml IL-1beta increased the level of glycosaminoglycan (GAG) released into the culture media, and up-regulated the activity and mRNA expression of matrix metalloproteinase 13 (MMP-13) and down-regulated the activity and mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in cartilage explants, as confirmed by the methods of GAG quantitation, MMP-13/TIMP-1 enzyme-linked immunosorbent assay (ELISA) and real-time quantitative RT-PCR. Treatment with 10 ng/ml IL-1beta resulted in marked apoptosis in chondrocytes, as demonstrated by decreased cell viability, occurrence of DNA laddering and increased caspase-3 activity and annexin V binding of phosphatidylserine. However, simultaneous treatment with SIN (10, 50 or 250 microM) inhibited the GAG release and the activity and mRNA expression of MMP-13, and enhanced the activity and mRNA expression of TIMP-1 in a dose-dependent manner in cartilage explants. Furthermore, DNA fragment, caspase-3 activity and apoptosis rate were down-regulated, and cell viability was up-regulated dose-dependently in chondrocytes. Thus, SIN has the protective capacity to antagonize cartilage degradation and chondrocyte apoptosis, which suggest that SIN may act as an agent for pharmacological intervention in the progress of OA.

Topics: Animals; Apoptosis; Cartilage, Articular; Caspase 3; Cell Survival; Cells, Cultured; Chondrocytes; Dose-Response Relationship, Drug; Glycosaminoglycans; Matrix Metalloproteinase 13; Morphinans; Osteoarthritis; Rabbits; Tissue Inhibitor of Metalloproteinase-1