forsythoside-b and forsythiaside

Chronic pain is frequently reported in clinical practice. Therefore, it is important to identify effective therapy to relieve pain. In this work, we selected Forsythoside B (FB), a phenylethanoid glycoside isolated from Forsythia suspensa (Thunb.) Vahl, to evaluate its effect in modulating inflammatory pain induced by complete Freund's adjuvant (CFA) and the involved mechanisms. We discovered that FB could attenuate inflammatory pain triggered by CFA injection and exert anti-anxiety effects. In detail, proinflammatory cytokines, consisting of IL-6 and TNF-α, were decreased after FB administration in the CFA-injected mice. Furthermore, the FB application ameliorated the activation of ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP), the microglia and astrocytes markers respectively. Therefore, our findings indicate that FB could be a promising treatment for chronic inflammatory pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Chronic Pain; Freund's Adjuvant; Glucosides; Hyperalgesia; Inflammation; Mice

In recent years, hypersensitivity reactions to the Shuanghuanglian injection have attracted broad attention. However, the componential chief culprits inducing the reactions and the underlying mechanisms involved have not been completely defined. In this study, we used a combination of approaches based on the mouse model, human umbilical vein endothelial cell monolayer, real-time cellular monitoring, immunoblot analysis, pharmacological inhibition, and molecular docking. We demonstrated that forsythoside A and forsythoside B contributed to Shuanghuanglian injection-induced pseudoallergic reactions through activation of the RhoA/ROCK signaling pathway. Forsythoside A and forsythoside B could trigger dose-dependent vascular leakage in mice. Moreover, forsythoside A and forsythoside B slightly elicited mast cell degranulation. Correspondingly, treatment with forsythoside A and forsythoside B disrupted the endothelial barrier and augmented the expression of GTP-RhoA, p-MYPT1, and p-MLC2 in a concentration-dependent manner. Additionally, the ROCK inhibitor effectively alleviated forsythoside A/forsythoside B-induced hyperpermeability in both the endothelial cells and mice. Similar responses were not observed in the forsythoside E-treated animals and cells. These differences may be related to the potential of the tested compounds to react with RhoA-GTPγS and form stable interactions. This study innovatively revealed that some forsythosides may cause vascular leakage, and therefore, limiting their contents in injections should be considered.

Topics: Animals; Caffeic Acids; Capillary Permeability; Cell Degranulation; Drugs, Chinese Herbal; Endothelial Cells; Glucosides; Glycosides; Humans; Mast Cells; Mice; Models, Molecular; Molecular Conformation; Molecular Structure; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Structure-Activity Relationship

Phenylethanoid glycosides, the main active ingredients in Fructus Forsythiae extract possesses strong antibacterial, antioxidant and antiviral effects, and their contents were higher largely than that of other ingredients such as lignans and flavones, but their absolute bioavailability orally was significantly low, which influenced clinical efficacies of its oral preparations seriously. In the present study, the absorption mechanism of phenylethanoid glycosides was studied using in vitro Caco-2 cell model. And the effect of chito-oligosaccharide (COS) on the intestinal absorption of phenylethanoid glycosides in Fructus Forsythiae extract was investigated using in vitro, in situ and in vivo models. The pharmacological effects such as antiviral activity improvement by COS were verified by MDCK cell damage inhibition rate after influenza virus propagation. The observations from in vitro Caco-2 cell showed that the absorption of phenylethanoid glycosides in Fructus Forsythiae extract so with that in monomers was mainly restricted by the tight junctions, and influenced by efflux transporters (P-gp and MRP2). Meanwhile, the absorption of phenylethanoid glycosides in Fructus Forsythiae extract could be improved by COS. Besides, COS at the same low, medium and high concentrations caused a significant, concentration-dependent increase in the Papp-value for phenylethanoid glycosides compared to the control group (p<0.05), and was all safe for the Caco-2 cells. The observations from single-pass intestinal perfusion in situ model showed that the intestinal absorption of phenylethanoid glycosides can be enhanced by COS. Meanwhile, the absorption enhancing effect of phenylethanoid glycosides might be saturable in different intestine sites. In pharmacokinetics study, COS at dosage of 25mg/kg improved the bioavailability of phenylethanoid glycosides in Fructus Forsythiae extract to the greatest extent, and was safe for gastrointestine from morphological observation. In addition, treatment with Fructus Forsythiae extract with COS at dosage of 25mg/kg prevented MDCK cell damage upon influenza virus propagation better than that of control. All findings above suggested that COS at dosage of 25mg/kg might be safe and effective absorption enhancer for improving the bioavailability of phenylethanoid glycosides and the antiviral activity in vitro in Fructus Forsythiae extract.

Topics: Animals; Antiviral Agents; Caco-2 Cells; Caffeic Acids; Dogs; Forsythia; Fruit; Glucosides; Glycosides; Humans; Influenza A virus; Intestinal Absorption; Madin Darby Canine Kidney Cells; Male; Molecular Structure; Oligosaccharides; Plant Extracts; Rats, Sprague-Dawley