Evaluation of antiinflammatory and antinociceptive activities of Lupeol Acetate isolated from Himatanthus drasticus (Mart.) Plumel - Apocynaceae (janaguba).

O Acetato de lupeol (FAL), isolado do lÃtex extraÃdo do caule de Himatanthus drasticus (APOCYNCEAE), à quimicamente classificado como sendo um triterpeno pentacÃclico pertencente à classe do lupano, foi avaliado em modelos de nocicepÃÃo e inflamaÃÃo. No teste das contorÃÃes abdominais induzidas por Ãcido acÃtico (10 ml/kg, i.p.) em camundongos, a FAL (50 e 100 mg/kg, i.p.) reduziu de forma significativa o nÃmero de contorÃÃes abdominais em 56 e 61%, respectivamente, e a indometacina (10 mg/kg, i.p.) reduziu em 66%. No teste da formalina, a FAL (25 e 50 mg/kg, i.p.) reduziu de forma significativa o tempo gasto pelo animal lambendo a pata, tanto na fase inicial (21 e 46,5%, respectivamente) quanto na fase tardia (57,6 e 61,3%, respectivamente) e a morfina (7,5 mg/kg, i.p.) reduziu em 62 e 91%, respectivamente. O prÃ-tratamento com Naloxona (2 mg/kg, i.p) reverteu de modo significativo, os efeitos da FAL e da morfina tanto na fase inicial quanto na tardia do teste da formalina. No edema de pata induzido por carragenina, a FAL (10, 25 e 50 mg/kg,i.p.) reduziu de modo significativo, o volume do edema na 1Â, 2 e 3 hora apÃs a aplicaÃÃo da carragenina (1%, 50μl, s.p.). AnÃlise histopatolÃgica do tecido de pata de camundongo submetido à carragenina, demonstrou reduÃÃes significativas no edema e do infiltrado celular. Na marcaÃÃo imunohistoquÃmica, em tecido de pata de camundongo submetida ao estÃmulo da carragenina, a FAL (50mg/kg, i.p.) promoveu uma discreta reduÃÃo na expressÃo de TNF- α, porÃm causou uma significante reduÃÃo dos nÃveis de iNOS teciduais. No edema de pata induzido por dextrano, a FAL (12,5 e 25 mg/kg, i.p.) reduziu de modo significativo, o volume do edema na 2 e 3 hora apÃs a aplicaÃÃo de dextrano (12%, 50μl, s.p.). Na peritonite induzida por carragenina, a FAL (1, 10 e 20 mg/kg, i.p.) diminuiu de forma significativa, o nÃmero de leucÃcitos em 56, 80 e 92%, respectivamente. A Pentoxifilina (1 e 25mg/kg, i.p.) inibiu em 39 e 68%, respectivamente o nÃmero de leucÃcitos. No teste da inibiÃÃo da atividade da enzima mieloperoxidase (MPO), a FAL (10, 25, 50 e 100 μg/ml) reduziu a atividade da MPO em 36, 80, 79 e 74 %, respectivamente. A FAL nÃo demonstrou atividade antioxidante no teste do DPPH. Em conjunto, esses dados revelam que a FAL apresenta atividade antinociceptiva, que pode ser explicada pela habilidade deste composto em mimetizar efeitos de opiÃides endÃgenos, e antiinflamatÃria, explicada pela diminuiÃÃo da expressÃo de TNF-α e iNOS, bem como pela diminuiÃÃo da atividades da mieloperoxidase, resultando na inibiÃÃo da migraÃÃo de leucocitÃria para o foco da inflamaÃÃo.The lupeol acetate (FAL), isolated from the latex extracted of the stem of Himatanthus drasticus (APOCYNCEAE) is chemically classified as a pentacyclic triterpene belonging to the lupane class, was evaluated in nociception and inflammation models. In the writhing test induced by acetic acid (10 ml/kg, i.p.) in mice, FAL (50 and 100 mg/kg, i.p.) significantly reduced the number of writhing in 56 and 61%, respectively, and indomethacin (10 mg/kg, i.p.) reduced by 66%. In the formalin test, FAL (25 and 50 mg/kg, i.p.) significantly reduced the time spent by the animal licking the paw, both in the initial phase (21 and 46.5%, respectively) and in the late phase (57 , 6, and 61.3%, respectively) and morphine (7.5 mg/kg, i.p.) reduced by 62 and 91%, respectively. Pretreatment with naloxone (2 mg/kg, i.p.) significantly reversed the effects of FAL and morphine in both the early and in late phase in formalin test. In the carrageenan induced paw oedema, FAL (10, 25 and 50 mg/kg, i.p.) reduced in significant way the oedema volume in the 1st, 2nd and 3rd hour after carrageenan application (1%, 50μl, s.p.). Histopathologic analysis of mice paw tissue subjected to carrageenan, showed significant reductions in oedema and cellular infiltration. In the immunohistochemical staining in mice paw tissue subjected to carrageenan stimulus, the FAL (50mg/kg, i.p.) induced a slight reduction in the expression of TNF-α, but caused a significant reduction of tissue iNOS levels. In the dextran induced paw oedema, FAL (12.5 and 25 mg/kg, i.p.) significantly reduced the oedema volume in the 2nd and 3rd hour after dextran application (12%, 50μl, s.p.). In carrageenan-induced peritonitis, FAL (1, 10 and 20 mg/kg, i.p.) significantly reduced the number of leukocytes at 56, 80 and 92%, respectively. Pentoxifylline (1 and 25mg/kg, i.p.) inhibited by 39 and 68%, respectively, the number of leukocytes. In the myeloperoxidase (MPO) enzyme inhibition test, FAL (10, 25, 50 and 100 μg/ml) reduced the activity of MPO at 36, 80, 79 and 74%, respectively. The FAL showed no antioxidant activity in DPPH test. Together, these data reveal that the FAL has antinociceptive activity, which can be explained by its ability in mimicking the endogenous opioids effects, and antiinflammatory, explained by TNF-α and iNOS expression decreased, as well as by the myeloperoxidase activity decreasing, resulting in inhibition of leukocyte migration to the focus of inflammation

Antiemetic activity of trans-ferulic acid possibly through muscarinic receptors interaction pathway: In vivo and in silico study

Current study was conducted to assess the effectiveness of the polyphenol trans-ferulic acid (TFA) as an antiemetic agent using in vivo and in silico methods. To evaluate this, we induced emesis in 3-day-old chicks through the oral administration of copper sulfate (CuSO4·5H2O) at a dose of 50 mg/kg. To ascertain the potential antiemetic mechanism of TFA, we employed various reference drugs such as domperidone (6 mg/kg), ondansetron (5 mg/kg), and hyoscine (21 mg/kg) as positive control groups, while the vehicle acted as a negative control group. TFA was administered orally at the doses of 25, 50 and 100 mg/kg body weight. Both the TFA and reference drug provided alone or in combined groups to assess their synergistic or antagonistic activity on the chicks. Molecular docking of TFA and the selected reference drugs was conducted against 5HT3, D2, H1, NK1, and mAChRs (M1-M5) receptors for determining binding affinity to the receptors. Active binding sites and drug-receptor interactions were predicted with the aid of various computational tools. Various pharmacokinetic features and drug-likeness of all the selected ligands were determined through the SwissADME online server. The results suggest that TFA diminishes the mean number of retches and enhances latency in the chicks at lower doses. In the combined drug therapy, TFA exhibited better antiemetic effects with ondansetron and hyoscine. In silico ADME proposed that TFA retains preferable drug-likeness and better pharmacokinetic properties to be a reliable lead. Additionally, TFA revealed the elevated binding affinity against mAChRs and the ligand (TFA) expressed the highest binding affinity (−7 kcal/mol) with the M5 receptor (6OL9). In conclusion, TFA demonstrated mild antiemetic effects in chicks, possibly through the mAChRs interaction pathway

Eicosapentaenoic acid and docosahexaenoic acid exert anti-inflammatory and antinociceptive effects in rodents at low doses

In the present study, we evaluated omega-3 polyunsaturated fatty acid (PUPA) (consisting of 20:5n-3 and 22:6n-3) properties on inflammation and nociception. Among the in vivo tests, writhing, formalin, and hot plate tests were conducted in mice, and carrageenan-induced paw edema, peritonitis, and Hargreaves tests were performed in rats. Following the carrageenan-induced edema, immunohistochemistry for tumor necrosis factor-alpha (TNF-alpha) was also carried out. We found that omega-3 PUPA treatment significantly decreased acetic acid-induced abdominal contortions as well as the first and second phases of the formalin test, which were reversed by naloxone. the carrageenan-induced rat paw edema was significantly reduced, along with neutrophil migration to the peritoneal cavity in the omega-3 PUPA treatment. in addition, there was a decrease in TNF-a immunostained cells in the inflamed paw with the omega-3 treatment compared with no omega-3. Withdrawal threshold in response to the thermal stimulation was significantly increased by the omega-3 treatment in the Hargreaves and hot plate tests. the in vitro studies (myeloperoxidase, lactate dehydrogenase, MTT cell viability and lipid peroxidation assays) were performed in human neutrophils. These studies showed that omega-3 treatment significantly decreased myeloperoxidase release, presented no cytotoxicity, and did not alter lipid peroxidation. Our study suggests that omega-3 PUPA anti-inflammatory and antinociceptive actions may involve inhibition of cyclooxygenases and microglial activation, leading to a reduced release of proinflammatory cytokines such as TNF-alpha, among other factors. the omega-3 PUFAs are potential candidates used alone or in combination with conventional nonsteroidal anti-inflammatory drugs, for the treatment of diseases where inflammation plays an important role. (C) 2013 Elsevier Inc. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Foundation for Research and Development of the State of Ceara (FUNCAP)Fac Med Estado Juazeiro do Norte FMJ, Juazeiro Do Norte, BrazilFed Univ São Paulo UNIFESP, São Paulo, BrazilFed Univ Ceara UFC, Fortaleza, Ceara, BrazilFed Univ São Paulo UNIFESP, São Paulo, BrazilWeb of Scienc