rosmarinic-acid and Edema

Cyclooxygenase-2 (COX-2) is an inducible enzyme that accelerates the biosynthesis of PGs during inflammation and has emerged as an important therapeutic target for anti-inflammatory drugs. Natural compounds may serve as a source of inspiration for pharmaceutical chemists and a foundation for developing innovative COX-2 inhibitors with fewer side effects. Therefore, the objective of this study was to identify the potent COX-2 inhibitor and anti-inflammatory activity of the Fimbristylis aestivalis whole plant extract (FAWE). The plant extract was found dominant with rosmarinic acid followed by catechin hydrate, syringic acid, rutin hydrate, (-) epicatechin, quercetin, myricetin, and catechol. FAWE exhibited considerable dose-dependent analgesic efficacy in all analgesic test models. FAWE also showed promising anti-inflammatory potential in carrageenan-induced inflammations in mice. This result was corroborated by molecular docking, revealing that the aforesaid natural polyphenols adopt the same orientation as celecoxib in the COX-2 active site. On the other hand, molecular dynamics (MD) simulations were performed between the most abundant components (rosmarinic acid, catechin hydrate, and syringic acid) and COX-2. Based on hydrogen bonding, RMSD, RMSF, radius of gyration, PCA, and Gibbs free energy landscape analysis, the results demonstrated that these compounds are very stable in the active site of COX-2, indicating substantial COX-2 inhibitory activity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Catechin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Mice; Molecular Docking Simulation; Plant Extracts; Rosmarinic Acid

Rosmarinic acid is a polyphenolic compound and main constituent of Rosmarinus officinalis and has been shown to possess antioxidant and anti-inflammatory properties. We aimed to evaluate the anti-inflammatory properties of rosmarinic acid and of an extract of R. officinalis in local inflammation (carrageenin-induced paw oedema model in the rat), and further evaluate the protective effect of rosmarinic acid in rat models of systemic inflammation: liver ischaemia-reperfusion (I/R) and thermal injury models. In the local inflammation model, rosmarinic acid was administered at 10, 25 and 50 mg/kg (p.o.), and the extract was administered at 10 and 25 mg/kg (equivalent doses to rosmarinic acid groups) to male Wistar rats. Administration of rosmarinic acid and extract at the dose of 25 mg/kg reduced paw oedema at 6 hr by over 60%, exhibiting a dose-response effect, suggesting that rosmarinic was the main contributor to the anti-inflammatory effect. In the liver I/R model, rosmarinic acid was administered at 25 mg/kg (i.v.) 30 min. prior to the induction of ischaemia and led to the significant reduction in the serum concentration of transaminases (AST and ALT) and LDH. In the thermal injury model, rosmarinic acid was administered at 25 mg/kg (i.v.) 5 min. prior to the induction of injury and significantly reduced multi-organ dysfunction markers (liver, kidney, lung) by modulating NF-κB and metalloproteinase-9. For the first time, the anti-inflammatory potential of rosmarinic acid has been identified, as it causes a substantial reduction in inflammation, and we speculate that it might be useful in the pharmacological modulation of injuries associated to inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Bronchoalveolar Lavage Fluid; Carrageenan; Cinnamates; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Inflammation Mediators; Lung; Male; Neutrophils; Oxidative Stress; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats, Wistar; Reperfusion Injury; Respiratory Burst; Rosmarinic Acid; Rosmarinus; Time Factors

In our previous report, rosmarinic acid (RA) was revealed to be an antidote active compound in Argusia argentea (family: Boraginaceae). The plant is locally used in Okinawa in Japan as an antidote for poisoning from snake venom, Trimeresurus flavoviridis (habu). This article presents mechanistic evidence of RA's neutralization of the hemorrhagic effects of snake venom. Anti-hemorrhagic activity was assayed by using several kinds of snake venom. Inhibition against fibrinogen hydrolytic and collagen hydrolytic activities of T. flavoviridis venom were examined by SDS-PAGE. A histopathological study was done by microscopy after administration of venom in the presence or absence of RA. RA was found to markedly neutralize venom-induced hemorrhage, fibrinogenolysis, cytotoxicity and digestion of type IV collagen activity. Moreover, RA inhibited both hemorrhage and neutrophil infiltrations caused by T. flavoviridis venom in pathology sections. These results demonstrate that RA inhibited most of the hemorrhage effects of venom. These findings indicate that rosmarinic acid can be expected to provide therapeutic benefits in neutralization of snake venom accompanied by heat stability.

Topics: Animals; Antivenins; Boraginaceae; Cell Survival; Cinnamates; Collagen Type IV; Depsides; Drug Stability; Edema; Fibrinogen; Hemorrhage; Hot Temperature; Human Umbilical Vein Endothelial Cells; Humans; Hydrolysis; Mice; Muscle, Skeletal; Phytotherapy; Plant Extracts; Rosmarinic Acid; Viper Venoms; Viperidae

Many plants are used in traditional medicine as active agents against various effects induced by snakebite. The methanolic extract from Cordia verbenacea (Cv) significantly inhibited paw edema induced by Bothrops jararacussu snake venom and by its main basic phospholipase A2 homologs, namely bothropstoxins I and II (BthTXs). The active component was isolated by chromatography on Sephadex LH-20 and by RP-HPLC on a C18 column and identified as rosmarinic acid (Cv-RA). Rosmarinic acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid [2-O-cafeoil-3-(3,4-di-hydroxy-phenyl)-R-lactic acid]. This is the first report of RA in the species C. verbenacea ('baleeira', 'whaler') and of its anti-inflammatory and antimyotoxic properties against snake venoms and isolated toxins. RA inhibited the edema and myotoxic activity induced by the basic PLA2s BthTX-I and BthTX-II. It was, however, less efficient to inhibit the PLA2 activity of BthTX-II and, still less, the PLA2 and edema-inducing activities of the acidic isoform BthA-I-PLA2 from the same venom, showing therefore a higher inhibitory activity upon basic PLA2s. RA also inhibited most of the myotoxic and partially the edema-inducing effects of both basic PLA2s, thus reinforcing the idea of dissociation between the catalytic and pharmacological domains. The pure compound potentiated the ability of the commercial equine polyvalent antivenom in neutralizing lethal and myotoxic effects of the crude venom and of isolated PLA2s in experimental models. CD data presented here suggest that, after binding, no significant conformation changes occur either in the Cv-RA or in the target PLA2. A possible model for the interaction of rosmarinic acid with Lys49-PLA2 BthTX-I is proposed.

Topics: Animals; Anti-Inflammatory Agents; Binding Sites; Caffeic Acids; Cinnamates; Cordia; Depsides; Edema; Enzyme Inhibitors; Lactates; Neurotoxins; Phospholipases A; Phospholipases A2; Rosmarinic Acid; Snake Venoms; Time Factors

Rosmarinic acid (RA) is a naturally occurring compound, isolated from Rosmarinus officinalis or Melissa officinalis which inhibits the in vitro immunohaemolysis of antibody-coated sheep erythrocytes by guinea pig serum. In further experiments this reduced immunohaemolysis was found to be due to inhibition of the C3-convertase of the classical complement pathway. The threshold concentration for inhibition of C3-convertase was 10(-6) mol/l. RA with an optimal inhibitory concentration between 5 and 10 mumol/l., resulting in about 70% inhibition of haemolysis. However, higher concentrations of RA were less effective at inhibiting C3-convertase. The inhibition may not be specific for C3-convertase, since another serine protease, elastase, was also weakly inhibited by RA in vitro. RA also exhibited inhibitory activity in three in vivo models in which complement activation plays a role. Thus, RA (0.316-3.16 mg/kg i.m.) reduced paw oedema induced by cobra venom factor (CVF) in the rat, and at 1-100 mg/kg p.o. inhibited passive cutaneous anaphylaxis in the rat. In addition, at 10 mg/kg i.m. RA impaired in vivo activation by heat-killed Corynebacterium parvum (i.p.) of mouse macrophages, as measured by the decreased capacity of the activated macrophages to undergo the oxidative burst. RA (0.1-10 mg/kg i.m.) did not inhibit t-butyl hydroperoxide-induced paw oedema in the rat, indicating selectivity for complement-dependent processes.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cinnamates; Complement Activating Enzymes; Complement Activation; Complement C3-C5 Convertases; Depsides; Edema; Elapid Venoms; Female; Guinea Pigs; In Vitro Techniques; Macrophage Activation; Male; Passive Cutaneous Anaphylaxis; Rats; Rats, Inbred Strains; Rosmarinic Acid