Evaluation of activities analgesic and anti-inflammatory of hexanic fraction of Agave sisalana

Orientador: Alba Regina Monteiro Souza BritoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: A dor é definida como uma sensação complexa e indefinida envolvendo múltiplos fatores como estilo de vida, ambiente. Muitas vezes a dor é produto de um processo inflamatório. As inflamações são uma resposta do sistema imune a diferentes estímulos, microorganismos, danos teciduais, estímulos miogênicos ou até traumas cirúrgicos que liberam mediadores endógenos. Ao receber o estímulo, diferentes enzimas como fosfolipases e ciclooxigenases originam mediadores inflamatórios (prostaglandinas, citocinas, leucotrienos) dando continuidade à cascata inflamatória muitas vezes de maneira exacerbada, que é caracterizada pelos cinco sinais cardinais da inflamação: calor, rubor, tumor, dor e perda de função. Para o tratamento das inflamações as drogas de primeira escolha são os antiinflamatórios não esteroidais (DAINES), que atuam na inibição da ciclooxigenase (COX-2), contudo, o uso das DAINES pode provocar o advento de úlceras pépticas, ou até mesmo falência renal e problemas cardíacos no caso dos inibidores seletivos da COX. Em inflamações crônicas utilizam-se os Glicocorticóides (GC), que são potentes antiinflamatórios, mas provocam efeitos colaterais sistêmicos como hipoglicemia, ação no sistema nervoso central e uma deficiência no sistema imune. A utilização de princípios ativos vegetais é uma alternativa para o controle das inflamações, entre elas destacam-se plantas da família Agavaceae, principalmente do gênero Agave, com destaque para Agave sisalana rica em saponinas esteroidais. As saponinas são uma classe de metabólitos secundários que apresentam diferentes funções terapêuticas, de grande interesse comercial e farmacológico. Esses compostos apresentam um núcleo esteroidal envolto por cadeias de açúcares denominado aglicona ou sapogenina. A partir das folhas da Agave sisalana obteve-se a fração hexânica de Agave sisalana (FHAS), que teve seu potencial terapêutico avaliado em diferentes testes de inflamação, algesia e toxicidade. A FHAS apresentou uma redução significativa (p<0,05) edema nos modelos agudos de inflamação; edema de orelha por Xilol e edema de pata induzido por carragenina. A FHAS também apresentou diminuições significativas no modelo crônico de inflamação Granuloma cotton pellet, que avalia a infiltração celular. Os valores obtidos no cotton pellet foram corroborados pelo modelo de pleurisia, em que também houve redução do infiltrado celular. A FHAS demonstrou um potencial antinociceptivo nos modelos de analgesia, porém com uma ação bem menor do que os fármacos padrão, o que indica que o mecanismo de ação parece não envolver atuação com receptores opióides em modelos de analgesia. Com relação à toxicidade a FHAS não apresentou aumento significativo (p<0,05) de proteínas plasmáticas. Na avaliação do peso animais nenhuma das doses da FHAS apresentou efeito significativo sobre a evolução ponderal de peso dos animais, como foi o caso do controle positivo GC, o que indica ausência de efeitos colaterais graves, semelhantes aos GC. Através da análise dos dados, indicam que ação antiinflamatória e analgésica encontrada deve-se a presença das sapogeninas esteroidais na FHAS, principalmente a hecogenina. Devido a esses resultados, novas avaliações serão feitas para elucidar o mecanismo de ação antiinflamatório apresenta ação semelhante aos GC, trazendo assim perspectivas de uso medicinal da Agave sisalana.Abstract: Pain is defined as complex and vague sensation that involves several factors such as life style and environment. Many times pain is a result of an inflammatory process. The inflammation an imune system response to different kind of stimulus, microorganisms, tissue injuries, miogenic stimulus or even cirurgic traumas, which release several endogens mediators. Receiving the stimulus, diferents enzymes as phospholipase and ciclogenasis, lead to inflammatory mediators (prostaglandins, citocins and leukotrienes) which continuity the inflammatory cascade, many times in an exarcebate manner, described by the five cardinals signs: Heat, redness, swelling, pain and loss of function. Inflammation Treatment the first choice in medicine are non steroidal antiinflammatory drugs (NSAIDS) that acts in inhibition of COX-2. However, the use of NSAIDS can bring peptic ulcers or kidney failure and cardiac problems in selective COX inhibitors. Chronic inflammation uses Glucocorticoids therapy that are powerfull drugs, but they provoque systemics side effects: as hypoglicemy, nervous system activity and immune system depression. The use of active compounds present in plants is a way to inflammatory controll, among them there are plants of Agavaceae family mainly Agave genus, such as Agave sisalana which is rich in steroidals saponins. Saponins are a secundary metabolic class that present several therapeutic functions, with a large comercial and pharmacological interest. These compounds present steroidal nucleus involved by sugar chains called algycone or sapogenins. From the Agave sisalana was taken Agave sisalana hexanic fraction (FHAS) that had its therapeutic potential evaluated in differents inflammatory, algesic and toxicity tests. FHAS showed significative responses for acute inflammatory models with antiedematogenic activity as xylene ear edema and carrageenan hind paw edema. FHAS also presents significative results chronic models like granuloma cotton pellet, which evaluate cell infiltration. The values gotten on cotton pellet were confirmed with pleurisy model, where there were reduction of cellular infiltrate. FHAS showed antinociceptive potential in algesic tests, with a smaller action than standard medicine, which indicates that the action mechanisms does not acts on opioid receptors in analgesic models. In connection to toxicity, FHAS does not present increase of plasmatics proteins, and animal weight evaluation none of FHAS doses showed significative effects considering weight up of animals. In case of positive control GC that indicates absence of side effects such GC. Throughout data analyses, the antiinflammatory and analgesic action founded is tempted by sapogenins presence on FHAS. These results need new evaluation to explain the antiinflammatory action mechanisms bringing new perspectives of Agave sisalana medical use.MestradoMestre em Biologia Funcional e Molecula

Applications of the hexanic fraction of Agave sisalana Perrine ex Engelm (Asparagaceae): control of inflammation and pain screening

The present study evaluated the anti-inflammatory and analgesic properties of Agave sisalana Perrine in classic models of inflammation and pain. The hexanic fraction of A. sisalana (HFAS) was obtained by acid hydrolysis followed by hexanic reflux. Anti-inflammatory properties were examined in three acute mouse models (xylene ear oedema, hind paw oedema and pleurisy) and a chronic mouse model (granuloma cotton pellet). The antinociceptive potential was evaluated in chemical (acetic-acid) and thermal (tail-flick and hot-plate test) models of pain. When given orally, HFAS (5, 10, 25 and 50 mg/kg) reduced ear oedema (p &lt; 0.0001; 52%, 71%, 62% and 42%, respectively). HFAS also reduced hind paw oedema at doses of 10 mg/kg and 25 mg/kg (p &lt; 0.05; 42% and 58%, respectively) and pleurisy at doses of 10 mg/kg and 25 mg/kg (41% and 50%, respectively). In a chronic model, HFAS reduced inflammation by 46% and 58% at doses of 10 mg/kg and 25 mg/kg, respectively. Moreover, this fraction showed analgesic properties against the abdominal writhing in an acetic acid model (at doses of 5-25 mg/kg) with inhibitory rates of 24%, 54% and 48%. The HFAS also showed an increased latency time in the hot-plate (23% and 28%) and tail-flick tests (61% and 66%) for the 25 mg/kg and 50 mg/kg doses, respectively. These results suggest that HFAS has anti-inflammatory and analgesic properties.26327

Study of indigo alkaloid on therapeutic of pain and inflammation

Orientador: Alba Regina Monteiro Souza BritoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A inflamação é uma resposta do sistema imune a patógenos ou a traumas físicos e químicos; sua evolução pode resultar em resolução dos danos ou tornar-se crônica. Como tal, trata-se de um fenômeno complexo envolvendo inúmeros mediadores como o NF-?B, que promove a liberação de citocinas e enzimas pró-inflamatórias seguidas por uma infiltração de leucócitos, resultando nos cinco sinais cardinais: calor, rubor, tumor (edema), dor e perda de função. A aplicação de metabólitos secundários de plantas é uma alternativa para o tratamento da dor e inflamação. Dentre estes metabólitos, os alcaloides recebem especial atenção já que a morfina é o mais potente analgésico conhecido. Neste trabalho o potencial anti-inflamatório e analgésico de outro alcaloide, o índigo (1.5, 3.0 e 6.0 mg/kg), obtido a partir de Indigofera truxillensis (Leguminosae), foi analisado em modelos de edema (de orelha induzido por xilol e ácido araquidônico, e de pata induzido por carragenina) e de migração celular (granuloma cotton pellet e pleurisia). Nesses modelos, o índigo apresentou redução significativa do edema e do infiltrado celular, principalmente de polimorfonucleares. Análises por ELISA (em lavado pleural) revelaram que o alcaloide diminuiu os níveis de MPO, nitrito e nitrato, PGE2 e TNF-?, além de apresentar redução significativa na expressão da COX-2 avaliadas por western blot e imuno-histoquímica. A redução dos mediadores sugere que o índigo possa ter ação anti-inflamatória envolvendo NF-?B, já que tal atividade foi confirmada por western blot. Nos modelos de dor inflamatória (teste de Randall & Selitto, contorções abdominais e formalina) o alcaloide novamente demonstrou resposta significativa, muito provavelmente por reduzir os mediadores inflamatórios envolvidos. O índigo aumentou a latência em modelos de dor induzido por estímulo térmico (tail flick e placa quente) e capsaicina, ambos envolvidos com atividade do TRPV1, mas não demonstrou interação alguma com receptores opioides no modelo de formalina com reversão por naloxona. Os resultados sugerem que o índigo possui ação anti-inflamatória devido um possível mecanismo de ação COX-2 e NF-?B. É provável que a redução desses mediadores contribua para ação analgésica na dor inflamatória e também para redução da dor periféricaAbstract: The inflammation is an immune system response to pathogens, chemical or physical traumas; this evolution may result in damage, or become chronic. It is a complex phenomenon, which involves several mediators, such as NF-?B that promotes the release of cytokines and pro-inflammatory enzymes followed by leukocyte infiltration; resulting in five cardinal signs: heat, redness, tumour, pain and loss of function. The application of secondary metabolites of plants is an alternative for treatment of pain and inflammation. Among the metabolites, the alkaloids receive special emphasis such as morphine, a potent analgesic. In this work, the anti-inflammatory and analgesic potential of indigo alkaloid (1.5, 3.0 e 6.0 mg/kg), obtained from Indigofera truxillensis (Leguminosae) was observed in edema models (xylene and arachidonic acid ear edema and carrageenan hind paw) and cellular infiltration (granuloma cotton pellet e pleurisy). In these models, indigo presented significant reduction of edema and cellular infiltration, mainly polimorphonuclears. ELISA analyses revealed that alkaloid decreased the levels of MPO, nitrite and nitrate, PGE2 and TNF-?, as well as the expression of COX-2 by western blot and immunohistochemistry. The reduction of mediators suggests that indigo could have anti-inflammatory an action that involves NF-?B, this activity was seen again by western blot. Randall & Selitto, abdominal writhing and formalin models of inflammatory pain were also performed and the alkaloid, over again, showed significant statistic response, probably by the reduction of inflammatory mediators. Indigo was also evaluated in neurogenic models of pain and demonstrated an increase of the latency in thermal stimuli (tail flick and hot plate tests) and capsaicin tests implicated with TRPV1 activity, however, the alkaloid did not show any interaction with opioid receptors in the formalin test with naloxone reversal. These results suggest that indigo has an anti-inflammatory action that may be involved with COX-2 and NF-?B, the reduction of these mediators contributed to the analgesic action in inflammatory pain and also to the reduction in peripheral painDoutoradoFarmacologiaDoutor em Farmacologi

Recent trends in pharmacological activity of alkaloids in animal colitis: potential use for inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic and disrupted inflammation of the gastrointestinal tract. IBD have two main conditions, Crohn's disease and ulcerative colitis, and have been extensively investigated in recent years. Antibiotics derived from salicylates, steroids, immunosuppressors, and anti-TNF therapy are part of the therapeutic arsenal for IBD. However, very often patients stop responding to treatments over the time. In this context, searching for alternative agents is crucial for IBD clinical management. Natural products derived from medicinal plants are an interesting therapeutic alternative, since several studies have proven effective treatments in animal models of intestinal inflammation. Several naturally occurring compounds are potent antioxidants, both as free radical scavengers and as modulators of antioxidant enzymes expression and activity. A number of natural compounds have also been proved to inhibit the release of proinflammatory cytokines, decreasing the activation of nuclear factor kappa B (NF-kappa B), which is important to the inflammatory response in IBD. The alkaloids are substances of a very diverse class of plant secondary metabolites; an extensive list of biological activities has been attributed to alkaloids, such as being anticholinergic, antitumor, diuretic, antiviral, antihypertensive, antiulcer, analgesic, and anti-inflammatory. In the present work, studies on the pharmacological activity of alkaloids in experimental models of IBD were reviewed2017sem informaçã

Therapy with lupeol, a natural pentacyclic triterpenoid, attenuates intestinal inflammation in rat

sem informação231S83S84Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference2016-12-08Orlando, FL, Estados Unidossem informaçã

Applications of the hexanic fraction of Agave sisalana Perrine ex Engelm (Asparagaceae): control of inflammation and pain screening

The present study evaluated the anti-inflammatory and analgesic properties of Agave sisalana Perrine in classic models of inflammation and pain. The hexanic fraction of A. sisalana (HFAS) was obtained by acid hydrolysis followed by hexanic reflux. Anti-inflammatory properties were examined in three acute mouse models (xylene ear oedema, hind paw oedema and pleurisy) and a chronic mouse model (granuloma cotton pellet). The antinociceptive potential was evaluated in chemical (acetic-acid) and thermal (tail-flick and hot-plate test) models of pain. When given orally, HFAS (5, 10, 25 and 50 mg/kg) reduced ear oedema (p < 0.0001; 52%, 71%, 62% and 42%, respectively). HFAS also reduced hind paw oedema at doses of 10 mg/kg and 25 mg/kg (p < 0.05; 42% and 58%, respectively) and pleurisy at doses of 10 mg/kg and 25 mg/kg (41% and 50%, respectively). In a chronic model, HFAS reduced inflammation by 46% and 58% at doses of 10 mg/kg and 25 mg/kg, respectively. Moreover, this fraction showed analgesic properties against the abdominal writhing in an acetic acid model (at doses of 5-25 mg/kg) with inhibitory rates of 24%, 54% and 48%. The HFAS also showed an increased latency time in the hot-plate (23% and 28%) and tail-flick tests (61% and 66%) for the 25 mg/kg and 50 mg/kg doses, respectively. These results suggest that HFAS has anti-inflammatory and analgesic properties

Mechanisms of action underlying the gastric antiulcer activity of the Rhizophora mangle L.

Ethnopharmacological relevance: Rhizophora mangle, the red mangrove, has long been known as a traditional antiulcer medicine. The present work evaluated the mechanisms of action involved in the anti-ulcer properties of the Rhizophora mangle bark extracts.Materials and methods: Gastroprotection of Rhizophora mangle was evaluated in rodent experimental models (ethanol). To elucidate the mechanisms of action the antisecretory action and involvement of NO, SH, mucus and PGE(2) were evaluated. The acetic acid-induced gastric ulcer model. Western blotting assay (COX-1, COX-2 and EGF) and immunohistochemical localization of HSP-70, PCNA and COX-2 were also used to evaluate the Rhizophora mangle healing properties.Results: Results showed that Rhizophora mangle bark crude extract (CE), as well as ethyl acetate (EtOAc) and butanolic fractions (BuOH) provided significant gastroprotection at all the tested doses. Thereby, the following protocols were performed using the lowest dose capable of producing the most effective gastroprotection, which was the BuOH 0.5 mg/kg (P<0.001). Several mechanisms are involved in the antiulcer activity of Rhizophora mangle, such as, participation of NO, SH and mucus. The enhancement of PGE2 levels and the upregulation of COX-2 and EGF seem to be directly linked to the antisecretory, cytoprotective and healing effects of BuOH. HSP-70 and PCNA are also involved in this cicatrisation process. No sign of toxicity was observed in this study, considering the analyzed parameters.Conclusion: Our study reinforces its traditional medicinal use. Considering that the current therapies are based on the use of antisecretory or cytoprotective drugs, the Rhizophora mangle arises as a promising alternative antiulcer therapy. (C) 2011 Elsevier B.V. All rights reserved