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Previous issue date: 2016-07-25 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Drugs currently used in pain and inflammation are responsible for a large number of adverse
effects, due to chronic use, producing in the patients a decrease of symptoms, but not an
overall improvement in quality of life, therefore it is of extreme importance to search for new
drugs. Piperine is the main active compound of black pepper (Piper nigrum), known in Brazil
as black pepper, popularly used by several beneficial effects. Studies in vitro and in vivo show
that piperine has functional involvement in antidepressant, hepatoprotective, anti-metastatic
antiparasitic, antithyroid, immunomodulatory, anti-inflammatory and analgesic effects. To
improve the selectivity and potency, molecular changes were made in the piperine, obtaining
the piperic acid. The objective of this study was to evaluate, through of models of acute and
chronic pain, and inflammation; a potential nociceptive and anti-inflammatory compound. In
the model of writhing induced by acetic acid was observed a percentage inhibition of writhes
of 77,9% compared to the control, in the highest dose tested (10mg / kg). In the formalin test,
the compound inhibited both phases of the test, wich the dose of 10mg/kg The inhibitory
effect was 30% in stage 1 and stage 2 at 67%. The increase in the latency time in tail flick test
had an earlier action compared to morphine and the piperic acid increased the latency time in
58% in 80min time in relation to baseline. We investigated the possible pathways involved in
the mechanism of action of the compound by prior administration of antagonists in the tail
flick test. We found that the muscarinic antagonist, atropine, was able to completely inhibit
the effect of the compound, demonstrating the involvement of the cholinergic pathway in the
mechanism of action. The opioid and nitrergic pathways and the potassium channel ATPdependent
are not involved in the mechanism of action, since these antagonists do not inhibit
the effect of the compound. The compound was able to inhibit capsaicin-induced nociception,
capsaicina is agonist TRPV1, in 45,34% demonstrating the involvement of TRPV1. The von
Frey test evaluate allodynia after chronic constriction of the sciatic nerve. In this test, the
compound did not show antinociceptive activity with the doses tested. The open field test was
used to determine the influence of the compound on the animal's mobility, and we observe
that the action of the compound did not interfere on animal's motor performance. The antiinflammatory
activity was evaluated in models of inflammation induced by carrageenan. In
the paw oedema test, the compound significantly reduced the oedema at doses of 5 and 10
mg/kg. In the air pouch test, we found that the leukocyte migration was reduced, as well as
the production of TNF-? and IL-1?. The piperic acid was shown to be selective for COX-1 in
the assessment of enzymatic activity of COX-1 and COX-2. We suggest that the effects of
piperine can be mediated primarily through the portion of the molecule related to piperic acid / Os f?rmacos atualmente utilizados em dor e inflama??o s?o respons?veis por um grande
n?mero de efeitos adversos, e devido ao uso cr?nico, fazem com que o paciente tenha uma
diminui??o dos sintomas, mas n?o uma total melhoria da qualidade de vida, sendo assim ? de
extrema import?ncia a busca por novos f?rmacos. A piperina ? o principal composto ativo da
pimenta preta (Piper nigrum), mais conhecida no Brasil como pimenta do reino,
popularmente utilizada por diversos efeitos ben?ficos. Estudos in vitro e in vivo demonstram
que a piperina tem envolvimento funcional como antidepressivo, hepatoprotetor,
antiparasit?rio antimetast?tico, antitiroidiano, imunomodulador, anti-inflamat?rio e
analg?sico. A fim de produzir melhora em sua seletividade e pot?ncia, altera??es moleculares
foram realizadas na piperina, obtendo-se ent?o o ?cido pip?rico. O objetivo deste trabalho foi
avaliar, atrav?s da execu??o de modelos experimentais de dor aguda, cr?nica e inflama??o, o
potencial farmacol?gico antinociceptivo e anti-inflamat?rio do composto. No modelo de
contor??es abdominais induzidas por ?cido ac?tico foi verificada um percentual de inibi??o
das contor??es de 77,9% comparado ao controle, na maior dose testada (10mg/kg). No
modelo da formalina o composto inibiu ambas as fases do modelo, com a dose de 10mg/kg o
efeito inibit?rio chegou a 30% na 1? fase e 67% na 2? fase. O aumento do tempo de lat?ncia
no modelo de retirada de cauda com o composto foi alcan?ado mais precocemente do que a
morfina, o ACP aumentou o tempo de lat?ncia em 58% no tempo de 80 min comparado a
linha de base na maior dose testada. Investigamos as poss?veis vias envolvidas no mecanismo
de a??o do composto atrav?s da administra??o pr?via de antagonistas, no modelo de retirada
de cauda. Verificamos que o antagonista de receptores muscar?nicos, atropina, foi capaz de
inibir completamente o efeito do composto, demonstrando a participa??o da via colin?rgica no
mecanismo de a??o. As vias opioide, nitr?rgica e o canal de pot?ssio dependente de ATP
parecem n?o estar envolvidas no mecanismo de a??o, visto que os antagonistas destas vias
n?o inibiram o efeito do composto. O composto inibiu a nocicep??o induzida pela capsaicina,
que ? agonista de receptores TRPV1 em 45,34%, demonstrando envolvimento de TRPV1. No
modelo de Von Frey avaliamos a alodinia ap?s a constri??o cr?nica do nervo ci?tico. Neste
modelo, o composto n?o demonstrou atividade antinociceptiva nas doses testadas. O modelo
de campo aberto foi usado para verificar a influ?ncia do composto sobre a mobilidade do
animal, e observamos que o mesmo n?o interfere no desempenho motor do animal. A
atividade anti-inflamat?ria foi avaliada em modelos de inflama??o induzido por carragenina.
No modelo de edema de pata, o composto reduziu o edema em 75% na dose de 10mg/kg. No
modelo da bolsa de ar subcut?nea verificamos que a migra??o leucocit?ria foi reduzida assim
como a produ??o de TNF-? e IL-1?. O ?cido pip?rico demonstrou ser seletivo para COX-1,
na avalia??o da atividade enzim?tica de COX-1 e COX-2. Podemos sugerir que os efeitos da
piperina podem ser mediados atrav?s da por??o da mol?cula referente ao ?cido pip?rico.
| Identifer | oai:union.ndltd.org:IBICT/oai:localhost:jspui/2159 |
| Date | 25 July 2016 |
| Creators | Oliveira, Poliana de Araujo |
| Contributors | Marinho, Bruno Guimar?es, Cortes, Wellington da Silva, Nascimento, Carlos Giovani de Oliveira |
| Publisher | Universidade Federal Rural do Rio de Janeiro, Programa Multic?ntrico de P?s-Gradua??o em Ci?ncias Fisiol?gicas, UFRRJ, Brasil, Instituto de Ci?ncias Biol?gicas |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da UFRRJ, instname:Universidade Federal Rural do Rio de Janeiro, instacron:UFRRJ |
| Rights | info:eu-repo/semantics/openAccess |
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