Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise

Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including Centella asiatica that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various in vitro and in vivo studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics

Anti-inflammatory activity of bartogenic acid containing fraction of fruits of Barringtonia racemosa Roxb. in acute and chronic animal models of inflammation

The fruits of Barringtonia racemosa are traditionally used in Indian medicine for the treatment of pain and inflammatory conditions. In this study, a fraction of ethyl acetate extract of fruits of B. racemosa (BREAF) was investigated for anti-inflammatory activity in experimental models of acute and chronic inflammation. Activity against acute inflammation was evaluated in inflammogens induced rat paw edema models. Whereas, effect in chronic inflammation was evaluated in cotton pellet granuloma and oxazolone induced delayed type hypersensitivity (DTH) model in mice. The BREAF exhibited dose dependent anti-inflammatory activity in both acute and chronic models at oral doses of 5, 10 and 20 mg/kg. BREAF inhibited both phases of carrageenan induced rat paw inflammation. The reduction in paw inflammation by BREAF was also evident in histamine and serotonin induced inflammation in rats. Effect of BREAF on DTH indicates inhibition of immune mediated inflammation. The reduction in cotton pellet granuloma by BREAF treatment shows inhibition of proliferative changes associated with chronic inflammation. Analysis of BREAF after chromatographic separations showed presence of bartogenic acid as a major constituent. Hence, it is proposed that anti-inflammatory effects of BREAF can be partially attributed to its bartogenic acid content. The minute doses at which this fraction shows anti-inflammatory effects emphasizes the need for further investigations on its efficacy in the immuno-inflammatory conditions

Homoeopathic drug dilutions of Thuja occidentalis attenuate complete Freund's adjuvant-induced arthritis in Wistar rats

Context: Thuja occidentalis is prescribed in Homoeopathy in treating rheumatoid arthritis. We speculated the anti-arthritic mechanism of Homoeopathic dilutions of Thuja occidentalis against the complete Freund's adjuvant (CFA)-induced arthritis in rats. Materials and Methods: Arthritis was induced (n = 28) by subplantar injection of 0.1 ml CFA in the right hind paw of rats. The oral dose of crude Thuja occidentalis was 30 mg/kg/b. i. d and that of Homoeopathic dilutions was 0.1 ml/b. i. d. Orally administered diclofenac at 5 mg/kg/day served as a standard. The treatments continued for 24 days. The severity of arthritis was determined weekly as rise in paw volume, mechanical allodynia and changes in body weight. On the 25th day, X-ray imaging of the arthritic paws was recorded, and the biopsy samples extracted from the paws were subjected to the estimation of pro-inflammatory cytokines and histological evaluations. Results: Thuja occidentalis Homoeopathic dilutions and its crude form protected rats against the CFA-induced arthritic lesions. The mother tincture, 6cH, 30cH and 200cH dilutions of Thuja occidentalis significantly reduced the CFA-induced rise in paw volume, reduced the mechanical allodynia and also reduced the levels of interleukin (IL) IL-1, IL-6 and tumour necrosis factor alpha in paw tissue. CFA-induced articular changes, oedema, cellular infiltrations and cartilage damage were reduced by Thuja occidentalis dilutions. The radiological images indicated that Thuja occidentalis treatment reduced the CFA-induced joint swelling, bone erosion and joint space narrowing. Conclusion: Our findings substantiate the anti-arthritic effects of Thuja occidentalis Homoeopathic dilutions against CFA-induced arthritis and indicate that Homoeopathic dilutions of Thuja occidentalis, particularly 6cH dilution, exert more potent anti-arthritic effects than its crude form

Two- and three-dimensional quantitative structure-activity relationships studies on a series of diuretics

Diuretics are an attractive class of drugs for the treatment of various disorders and in combination with some cardiovascular drugs. In the present work, 2D and 3D quantitative structure-activity relationship studies have been conducted on a series of diuretics. Significant correlation coefficients (r2 = 0.81 and q2 = 0.65, r2 = 0.91 and q2 = 0.85) were obtained, indicating potential of the models generated for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contributions should be useful for the design of diuretics having improved potency.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Pentacyclic Triterpenoids Inhibit IKKβ Mediated Activation of NF-κB Pathway: In Silico and In Vitro Evidences.

Pentacyclic Triterpenoids (PTs) and their analogues as well as derivatives are emerging as important drug leads for various diseases. They act through a variety of mechanisms and a majority of them inhibit the nuclear factor kappa-beta (NF-κB) signaling pathway. In this study, we examined the effects of the naturally occurring PTs on IκB kinase-β (IKKβ), which has great scientific relevance in the NF-κB signaling pathway. On virtual screening, 109 PTs were screened through the PASS (prediction of activity spectra of substances) software for prediction of NF-κB inhibitory activity followed by docking on the NEMO/IKKβ association complex (PDB: 3BRV) and testing for compliance with the softened Lipinski's Rule of Five using Schrodinger (LLC, New York, USA). Out of the projected 45 druggable PTs, Corosolic Acid (CA), Asiatic Acid (AA) and Ursolic Acid (UA) were assayed for IKKβ kinase activity in the cell free medium. The UA exhibited a potent IKKβ inhibitory effect on the hotspot kinase assay with IC50 of 69 μM. Whereas, CA at 50 μM concentration markedly reduced the NF-κB luciferase activity and phospho-IKKβ protein expressions. The PTs tested, attenuated the expression of the NF-κB cascade proteins in the LPS-stimulated RAW 264.7 cells, prevented the phosphorylation of the IKKα/β and blocked the activation of the Interferon-gamma (IFN-γ). The results suggest that the IKKβ inhibition is the major mechanism of the PTs-induced NF-κB inhibition. PASS predictions along with in-silico docking against the NEMO/IKKβ can be successfully applied in the selection of the prospective NF-κB inhibitory downregulators of IKKβ phosphorylation

Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals

Inflammation is one of the common events in the majority of acute as well as chronic debilitating diseases and represent a chief cause of morbidity in today’s era of modern lifestyle. If unchecked, inflammation leads to development of rheumatoid arthritis, diabetes, cancer, Alzheimer’s disease, and atherosclerosis along with pulmonary, autoimmune and cardiovascular diseases. Inflammation involves a complex network of many mediators, a variety of cells, and execution of multiple pathways. Current therapy for inflammatory diseases is limited to the steroidal and non-steroidal anti-inflammatory agents. The chronic use of these drugs is reported to cause severe adverse effects like gastrointestinal, cardiovascular, and renal abnormalities. There is a massive need to explore new anti-inflammatory agents with selective action and lesser toxicity. Plants and isolated phytoconstituents are promising and interesting sources of new anti-inflammatories. However, drug development from natural sources has been linked with hurdles like the complex nature of extracts, difficulties in isolation of pure phytoconstituents, and the yield of isolated compounds in minute quantities that is insufficient for subsequent lead development. Although various in-vivo and in-vitro models for anti-inflammatory drug development are available, judicious selection of appropriate animal models is a vital step in the early phase of drug development. Systematic evaluation of phytoconstituents can facilitate the identification and development of potential anti-inflammatory leads from natural sources. The present review describes various techniques of anti-inflammatory drug screening with its advantages and limitations, elaboration on biological targets of phytoconstituents in inflammation and biomarkers for the prediction of adverse effects of anti-inflammatory drugs. The systematic approach proposed through present article for anti-inflammatory drug screening can rationalize the identification of novel phytoconstituents at the initial stage of drug screening programs

Docking results of PTs on IKKβ based on glide dock score and number of hydrogen bond interactions (Schrodinger 9.0).

<p>Compounds that pass the docking filter are highlighted in bold; compounds that do not pass the docking filter are highlighted in italic</p><p>Docking results of PTs on IKKβ based on glide dock score and number of hydrogen bond interactions (Schrodinger 9.0).</p

CA, AA and UA inhibited IFN-γ release from LPS stimulated RAW cells.

<p><i>In vitro</i> (supernatant) level of IFN-γ in LPS stimulated RAW cells treated with CA, AA and UA detected through indirect ELISA. Y axis represents the absorbance at 450 nm. Data represented as mean ± SD of three independent experiments. **P < 0.01 (ANOVA) as compared with LPS treated group.</p

CA, AA and UA affect viability of RAW 264.7 cells as evident in MTT assay.

<p>Cytotoxicity was evaluated by MTT assay after exposure of RAW 264.7 cells to increasing concentrations of CA (■), AA (♦) and UA (●) (10 to 150 μM) for 24 h. Cells were plated in each well (10,000 cells/well) of the 96-well tissue-culture plates, after 70% confluence, cells were treated with different concentrations of CA (■), AA (♦) and UA (●) for 24 h. After drug treatment MTT assay was performed as described under materials and methods section. Data were plotted as percent viability (% control).</p