morphinans and Edema

Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that sinomenine (SIN) decreased prostaglandin (PG)E

Topics: A549 Cells; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cell Culture Techniques; Cell Survival; Edema; Female; Gene Expression; Macrophages, Peritoneal; Male; Mice, Inbred DBA; Morphinans; Prostaglandin-E Synthases; Rats, Sprague-Dawley; Transfection

Milonine is an alkaloid of Cissampelos sympodialis Eichl. (Menispermaceae), a plant used in the northeast of Brazil to treat allergies such as asthma, rhinitis, and other conditions. Previously, several alkaloids were isolated from its roots and leaves with pharmacological properties in asthma and acute inflammation models. Therefore, the aim of this study was to evaluate the milonine effect on mast cells degranulation in vivo and in vitro. Swiss mice (n = 8) were used in models of paw edema induced by carrageenan, compound 48/80, or histamine. One hour before challenge, the animals were treated with milonine (at different doses) or standard drugs and, at different time points, the edema formation was measured. In addition, other different methods, such as anaphylactic shock reaction and scratching behavior models both induced by compound 48/80, a mast cell degranulator, were used to assess milonine effect histamine release in vivo. Moreover, milonine effect on mast cell degranulation in vitro was also carried out. Firstly, it was observed that milonine significantly decreased the carrageenan edema formation only at the beginning of the reaction (i.e., up to 2 h after challenge). Furthermore, this alkaloid decreased the edema induced by compound 48/80, maintained the paw tissue integrity, without modulating histamine-induced paw edema. In anaphylactic shock reaction, milonine increased the time of animal survival when compared with compound 48/80 group. Milonine also significantly decreased the scratching behavior induced by compound 48/80 with decreasing of mast cell degranulation in vitro. Therefore, these data indicated that milonine presents anti-allergic properties by decreasing mast cell degranulation rather than acting on histamine effect.

Topics: Alkaloids; Anaphylaxis; Animals; Anti-Allergic Agents; Cissampelos; Edema; Histamine Release; Mast Cells; Mice; Morphinans; Pruritus

The investigation was undertaken to evaluate the effect of sinomenine (Sin) on experimental adjuvant arthritis rats stimulated by Freund's complete adjuvant and explore the corresponding potential molecular mechanism. The content of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6 were detected. Besides, canonical nuclear factor kappa B (NF-κB) pathway was also assessed to evaluate the antiarthritic potential of sinomenine. Pathological sections of rat paws showed sinomenine and diclofenac sodium significantly alleviated articular cartilage lesion, cellular infiltration, epithelial cell degeneration, synovial tissue vasodilation and congestion. The phosphorylations of inhibitor of kappaB alpha and NF-κB subunit p65 were downregulated with the treatment of sinomenine in dose dependent manners, as well as proinflammatory cytokines. Therefore, it was assumed that sinomenine might be a new therapeutic candidate to treat arthritis. © 2016 IUBMB Life, 68(6):429-435, 2016.

Topics: Adaptor Proteins, Signal Transducing; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cytokines; Edema; Freund's Adjuvant; I-kappa B Proteins; Morphinans; Nuclear Proteins; Nuclear Receptor Interacting Protein 1; Phosphorylation; Rats, Sprague-Dawley; Transcription Factor RelA

Sinomenine is an isoquinoline-type alkaloid found in Sinomenium acutum (Thunb.) Rehd. et Wils and S. acutum (Thunb.) Rehd. et Wils var. cinereum Rehd. et Wils. When used as a medicine, this compound exhibits anti-inflammatory properties; however, sinomenine's use as a medication is limited by side effects, a short half-life, and low efficacy. Owing to these limits, attempts have been made to synthesize sinomenine derivatives with enhanced efficacy. In this study, the anti-inflammatory effects of novel sinomenine derivatives (S1a-S1f) were examined on the basis of lipopolysaccharide-induced inflammatory factor expression in Raw264.7 cells, dimethylbenzene-induced ear oedema, and Evan's blue leakage in mice, and carrageenan-induced paw oedema in rats. Compared with sinomenine, the derivatives significantly inhibited the expression of the inflammatory factors IL-1β and IL-6 at the transcriptional and translational levels. Topical application of 3.250mg/kg of the derivatives also alleviated ear oedema. Compared with the vehicle, the derivatives significantly inhibited carrageenan-induced rat paw oedema after 6h. Among the derivatives, S1a exhibited the most potent anti-inflammatory activity. S1a also significantly increased the sinomenine-induced inhibition of Evan's blue leakage. Thus, S1a may elicit the strongest anti-inflammatory effects of the tested compounds. Based on these results, further development of this compound may be warranted.

Topics: Animals; Anti-Inflammatory Agents; Capillary Permeability; Carrageenan; Coloring Agents; Edema; Evans Blue; Foot; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Mice; Morphinans; Rats; Rats, Sprague-Dawley; Sinomenium; Tumor Necrosis Factor-alpha; Xylenes

Sinomenine (1) is currently used for the treatment of rheumatoid arthritis (RA) in China and there is still room for the improvement of its efficacy. In present study, capillary based microfluidic system was effectively applied for the syntheses of two novel series of sinomenine derivatives. The Heck reactions in microreactor gave much higher conversions compared to the batch ones. The two-step synthesis of the isoxazoline in microreactor greatly shortened the reaction time without any isolation of intermediates. The inhibitory activity of synthesized compounds on the TNF-α-induced nuclear factor kappa B (NF-κB) activation was evaluated in vitro. Among the compounds, 3c and 3g showed the potent inhibitory activity. Furthermore, 3g exhibited the antiinflammatory effect in vivo.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cell Survival; Dose-Response Relationship, Drug; Edema; Mice; Mice, Inbred ICR; Microfluidic Analytical Techniques; Models, Molecular; Morphinans; NF-kappa B; NIH 3T3 Cells; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Sinomenine transdermal patch was prepared and its properties were studied. The patches were produced by salivation method. The releasing rate in vitro of the patch was determined by HPLC. Peel test was used to evaluate the adhesion. Acute skin irritation test was performed in comparison with formalin (0.8%) by using mouse model. The Sinomenine TDDS Patch was prepared. The releasing rate in vitro followed the Higuchi equation (r>0.99), the releasing amount was beyond 90% in 24h. The peel adhesion to steel (N/25 mm) is 10 or above. The skin irritation tests showed negligible erythema and edema. The Sinomenine transdermal patch was prepared successfully and it may be beneficial for topical use.

Topics: Adhesiveness; Administration, Cutaneous; Animals; Antirheumatic Agents; Chemistry, Pharmaceutical; Dosage Forms; Edema; Erythema; Excipients; Kinetics; Male; Mice; Morphinans; Permeability; Skin; Skin Absorption; Skin Irritancy Tests; Solubility; Tissue Adhesives

To provide basic data for the synthesis of new sinomenine derivatives.. The C ring in sinomenine was modified.. Seven compounds were prepared and screened for anti-inflammatory and analgesic activities. Compounds 2 and 5 showed better activities.. Modification of the C ring in sinomenine should be worthy to be studied further.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Edema; Mice; Molecular Conformation; Molecular Structure; Morphinans; Pain Measurement; Plants, Medicinal; Rats; Sinomenium