Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-04-20T13:30:13Z No. of bitstreams: 2 Dissertação - Daiany Priscilla Bueno da Silva - 2015.pdf: 1122736 bytes, checksum: fc98524b1ad5d0e3a0cb2e1cc87bc933 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-04-20T13:32:30Z (GMT) No. of bitstreams: 2 Dissertação - Daiany Priscilla Bueno da Silva - 2015.pdf: 1122736 bytes, checksum: fc98524b1ad5d0e3a0cb2e1cc87bc933 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-04-20T13:32:30Z (GMT). No. of bitstreams: 2 Dissertação - Daiany Priscilla Bueno da Silva - 2015.pdf: 1122736 bytes, checksum: fc98524b1ad5d0e3a0cb2e1cc87bc933 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-02-25 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The piperazines derivatives are an important class of chemical compounds with a broad spectrum of biological activities such as anti-infectious activity, anti-carcinogenic, anti-nociceptive, anti-hypertensive, anxiolytic and vasorelaxant and are attractive candidates for development of new analgesics and anti-inflammatories drugs. The aim of this study was evaluate the effects of piperazine compound LQFM-008 (4-[(1-phenyl-1H-pyrazol-4-yl) methyl]1-piperazine carboxylic acid ethyl ester) in acute tests of nociception and inflammation and characterize that the mechanisms are involved in the antinociceptive effect. For this study were used male mice weighing between 25 and 35g. In the formalin test, the treatments with LQFM-008 at doses of 48 and 96 μmol/kg (p.o.) reduced the licking time at both neurogenic and inflammatory phases of this test. The anti-inflammatory activity was confirmed, since LQFM-008 at doses of 48 and 96 μmol/kg (p.o.) reduced the formation of paw edema induced by carrageenan at all hours of the test and LQFM-008 in pleurisy test at dose of 96 μmol/kg (p.o.) also reduced leukocyte migration and protein exudation. In the tail-flick and the hot plate tests, the treatment with LQFM-008 at doses of 48 and 96 μmol/kg (p.o.) increased the latency to thermal stimulus, suggesting the involvement of central mechanisms in the antinociceptive effect LQFM-008. The pre-treatment of animals with naloxone (7.5 μmol/kg s.c.) reversed the antinociceptive effect of LQFM-008 only in the first phase of the formalin test, however, the pre-treatment with NAN-190 (1.3 μmol/kg i.p.) and PCPA (500 μmol/kg i.p.) reversed the antinociceptive effect of LQFM-008 in both phases of the test. Thus, the piperazine derivative LQFM-008 exhibit antinociceptive and anti-inflammatory activities in acute test and the antinociceptive effect is resulting from a central action with involvement of opioid receptors and the serotonin pathway. / Os derivados piperazínicos constituem uma importante classe de compostos químicos com largo espectro de atividades biológicas, tais como atividade anti-infecciosa, anti-cancerígena, antinociceptiva, anti-hipertensiva, vasorrelaxante e ansiolítica, tornando-se candidatos atrativos para desenvolvimento de novos fármacos analgésicos e anti-inflamatórios. O objetivo do presente trabalho foi avaliar os efeitos do composto piperazínico LQFM-008 (4-((1-fenil-1H-pirazol-4-il) metil) piperazina-1-carboxilato) em testes agudos de nocicepção e inflamação, buscando caracterizar quais os mecanismos de ação estariam envolvidos no efeito antinociceptivo. Para este estudo foram utilizados camundongos machos, pesando entre 25 e 35g. No teste da formalina os tratamentos com LQFM-008 nas doses de 48 e 96 μmol/kg (v.o.) reduziram o tempo de reatividade à dor tanto na fase neurogênica quanto na fase inflamatória do teste. A atividade anti-inflamatória foi confirmada, uma vez que LQFM-008 nas doses de 48 e 96 μmol/kg (v.o.) reduziu a formação do edema de pata induzido por carragenina em todas as horas deste teste e no teste de pleurisia LQFM-008 na dose de 96 μmol/kg também reduziu a migração de leucócitos e a exsudação proteica. Nos testes de flexão de cauda e da placa quente, o tratamento com LQFM-008 48 e 96 μmol/kg (v.o.) aumentou a latência ao estímulo térmico, sugerindo o envolvimento de mecanismos centrais no efeito antinociceptivo de LQFM-008. O pré-tratamento dos animais com naloxona (7,5 μmol/kg s.c.) reverteu o efeito antinociceptivo de LQFM-008 apenas na primeira fase do teste da formalina, no entanto, os pré-tratamentos com NAN-190 (1,3 μmol/kg i.p.) e PCPA (500 μmol/kg i.p.) reverteram o efeito antinociceptivo de LQFM-008 em ambas as fases do teste. Assim o derivado piperazínico LQFM-008 apresenta atividade antinoceptiva e anti-inflamatória em testes agudos, sendo efeito antinociceptivo decorrente de uma ação central com envolvimento dos receptores opióides e da via serotoninérgica.

Les préparations de Viscum album (VA), connu sous le nom vernaculaire de gui européen, sont fréquemment utilisées en support des traitements anticancéreux, principalement pour améliorer la qualité de vie des malades et réduire la croissance des tumeurs. Elles sont connues pour exercer des effets anti-tumoraux. Il existe de plus en plus de données scientifiques faisant état de liens étroits entre cancer et inflammation. Étant donné que la prostaglandine E2 (PGE2) induite par la cyclo-oxygénase 2 (COX-2) joue un rôle clef dans l’inflammation, j’ai exploré la régulation du système COX-2-PGE2 par VA et ses mécanismes sous-jacents. J’ai montré que VA exerce ses effets anti-inflammatoires en inhibant sélectivement l’expression de COX-2 et en diminuant la production de PGE2 qui en découle, par le biais d’une déstabilisation de l’ARNm de COX-2. En plus de leurs propriétés cytotoxiques, il a été montré que les préparations de VA ont également des effets immunostimulants. Les différentes préparations de VA sont hautement hétérogènes du fait de leurs compositions biochimiques qui varient selon la récolte, l’espèce de l’arbre hôte et les méthodes de préparation qui peuvent influer sur leur efficacité clinique. De ce fait, j’ai réalisé une étude comparative sur cinq préparations de VA dans le but d’analyser leurs capacités de maturation et d’activation des cellules dendritiques (DC) qui peuvent à leur tour présenter une réponse immunitaire anti-tumorale. Les résultats ont montré que parmi les cinq préparations,VA Qu Spez induit de manière significative l’activation des DC et la sécrétion de cytokines pro-inflammatoires telle que l’IL-6, l’IL-8 et le TNF-α qui induisent la production d’IFN-γ,orientant de ce fait la réponse immunitaire vers une réponse Th1. L’orchestration de la11fonction des cellules myélomonocytiques est un élément central à l’interface entre inflammation et cancer. Il constitue un paradigme expliquant la plasticité et la fonction des macrophages. Mon étude met en évidence l’influence de VA Qu Spez sur la polarisation des macrophages qui passent d’un état alternatif (M2) à un état dit classique (ou M1). Les macrophages M2 sont connus pour polariser les réponses immunitaires Th2, pour participer à l’élimination des parasites, pour diminuer l’inflammation, pour promouvoir le remodelage tissulaire et la progression des tumeurs et pour avoir des fonctions immunorégulatrices. Les macrophages M1 sont impliqués dans la réponse Th1, favorisent la résistance aux pathogènes intracellulaires et aux tumeurs et promeuvent des réactions de désagrégation tissulaires. L’ensemble de ces résultats permet de comprendre les propriétés anti-inflammatoires et immunostimulantes des préparations de VA. Des recherches complémentaires permettront d’améliorer les stratégies d’utilisation thérapeutique de VA et son utilisation dans les soins de support aux traitements anticancéreux. / Viscum album (VA) preparations, commonly known as European mistletoe, are frequentlyused as complementary therapy in cancer, mainly to improve quality of life of the patients andto reduce the tumor growth. They are known to exert anti-tumoral effects. There is increasing evidence of the convoluted connection of cancer and inflammation. As cyclooxygenase-2(COX-2)-induced prostaglandin E2 (PGE2) plays a key role in the inflammation, I explored the regulation of COX-2-PGE2 axis by VA and underlying mechanisms. I found that VA exerts anti-inflammatory effects by selectively inhibiting COX-2 expression and ensuing PGE2 production. Inhibition of COX-2 expression implicates COX-2 mRNA destabilisation. In addition to their cytotoxic properties, they have also been shown to have immunostimulatory properties. Each VA preparations are highly heterogeneous because oftheir chemical composition which varies depending on the time of harvest, species of host treeand manufacturing methods, together which might influence clinical efficacy of VA.Therefore I performed a comparative study involving five different preparations of VA concerning maturation and activation of dendritic cells (DCs) which in turn may manifestanti-tumoral immune response. Results showed that among all five preparations, VA Qu Spez significantly induces DC activation, secretion of pro-inflammatory cytokines such as IL-6, Il-8 and TNF-α, enhancing IFN-γ production hence promoting Th1 immune response. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. My study reveals the effect of VA Qu Spez in switching the M2 macrophages which are known to participate inpolarizing Th2 responses, help with parasite clearance, dampen inflammation, promote tissue remodelling and tumor progression and have immunoregulatory functions, towards classicallyactivated M1 macrophages which are part of a polarized Th1 response and mediate resistance13to intracellular pathogens and tumors and elicit tissue-disruptive reactions. These results together should assist in understanding the anti-inflammatory and immunostimulatory properties of VA preparations and further research is warranted to improve the therapeutic strategies of use of VA and their role as complimentary therapy in cancer.