INTRODUCTION: Endometriosis is a disease characterized by the presence of extrauterine endometrial implants. Its etiopathogenesis isn’t fully understood, it’s believed that immunological and hormonal factors influence the peritoneal environment, preventing the elimination of refluxed endometrial cells during the menstrual period. In addition, endometriosis has been reported as an inflammatory process and some studies have demonstrated the inflammatory resolutive mediators involvement in endometrial physiology and suggest that they may be involved in the endometriosis progression by anti-inflammatory and antiangeogenic action. OBJECTIVE: To characterize Annexin A1 (ANXA1), FPR2/ALX and cytokines expression in peritoneal endometriosis and to clarify their role in its etiology. METHODS: A laboratory analysis was performed human samples with forty women in reproductive age (22 patients with endometriosis and 18 control women) that had undergone laparoscopic surgery. Peritoneal biopsy e fluid aspirations from endometriosis and control samples were analyzed for the expression of ANXA1, FPR2/ALX and cytokines. ANXA1 and FPR2 / ALX levels were measured by Western blotting and interleukin 1ß (IL-1ß), 4 (IL-4), 6 (IL-6) e 10 (IL-10) were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: The present study identified the presence in human peritoneal tissue of ANXA1 and FPR2 / ALX both in healthy condition and in women with peritoneal endometriosis, however, was lower in endometriosis samples than in control samples. By quantifying the IL-6 and IL-1β cytokines in the peritoneal fluid by ELISA, this study identified a higher IL-6 concentration in endometriosis group, but no significative difference in IL-1ß levels. In all samples, levels of IL-4 and IL-10 cytokines were below the detection level of the method used. CONCLUSION: These results indicate that the reduction of the inflammatory resolution mediators may be responsible for the inflammatory process perpetuation, maintenance and worsening of endometriosis. / Submitted by Lia Karina Volpato (lia.volpato@unisul.br) on 2018-03-13T15:25:32Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Lia Karina Volpato.pdf: 23378759 bytes, checksum: c029f98522ccc30394074d42329f7c3b (MD5) / Approved for entry into archive by Caroline Correa da Cruz (caroline.cruz@unisul.br) on 2018-03-13T18:35:21Z (GMT) No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Lia Karina Volpato.pdf: 23378759 bytes, checksum: c029f98522ccc30394074d42329f7c3b (MD5) / Made available in DSpace on 2018-03-13T18:35:21Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Lia Karina Volpato.pdf: 23378759 bytes, checksum: c029f98522ccc30394074d42329f7c3b (MD5) Previous issue date: 2017 / Endometriose é uma doença caracterizada pela presença de implantes endometriais extrauterinos. Sua etiopatogenia não está totalmente esclarecida, acredita-se que fatores imunológicos e hormonais influenciam o ambiente peritoneal, impedindo a eliminação das células endometriais refluídas durante o período menstrual. Além disso, a endometriose tem sido relacionada como um processo inflamatório e alguns estudos têm demonstrado o envolvimento de mediadores pró-resolutivos da inflamação na fisiologia endometrial e sugerem que possam estar envolvidos na progressão da endometriose por ação anti-inflamatória e antiangeogênica. OBJETIVO: Caracterizar a densidade de anexina A1 (ANXA1), FPR2 / ALX e citocinas na endometriose peritoneal e esclarecer seu papel etiológico. MÉTODOS: Foi realizado um estudo de análise laboratorial com amostras humanas de quarenta mulheres em idade reprodutiva (22 pacientes com endometriose e 18 mulheres controle) submetidas à cirurgia laparoscópica. Foram realizadas biópsia peritoneal e aspiração de fluido peritoneal em amostras de endometriose e de controle, que foram analisadas quanto à densidade de ANXA1, FPR2 / ALX e citocinas. Os níveis de ANXA1 e FPR2 / ALX foram medidos por Western blott e as interleucinas 1ß (IL-1ß), 4 (IL-4), 6 (IL-6) e 10 (IL-10) foram quantificadas por ensaio de imunoabsorção enzimática (ELISA). RESULTADOS: O presente estudo identificou a presença no tecido peritoneal humano de ANXA1 e FPR2 / ALX em condições saudáveis e em mulheres com endometriose peritoneal, no entanto, a densidade foi menor nas amostras de endometriose do que nas amostras de controle. Este estudo identificou uma maior concentração de IL-6 no fluido peritoneal do grupo com endometriose, mas não houve diferença significativa nos níveis de IL-1β. Em todas as amostras, os níveis de citocinas IL- 4 e IL- 10 estiveram abaixo do nível de detecção do método utilizado. CONCLUSÃO: Estes resultados indicam que a redução dos mediadores de resolução inflamatória pode ser responsável pela perpetuação, manutenção e agravamento do processo inflamatório da endometriose.

La maladie de Parkinson (MP) est un trouble dégénératif du système nerveux central qui affecte principalement les personnes âgées. Son principal traitement est la L-3,4-dihydroxyphénylalanine (L-DOPA), qui malheureusement provoque des problèmes handicapants tels que les dyskinésies et les psychoses à la suite d’une administration chronique. Peu de traitements sont disponibles pour réduire efficacement ces complications et certains interfèrent avec l’effet thérapeutique de la L-DOPA, alors que d’autres induisent des effets secondaires potentiellement dangereux pour la vie des patients. Il est donc crucial de découvrir de nouvelles cibles thérapeutiques. Des études cliniques et précliniques ont montré que le site de liaison de la glycine du récepteur N-méthyl-D-aspartate (NMDA) est une cible thérapeutique prometteuse pour les problèmes moteurs de la MP. En effet, la stimulation de celui-ci augmenterait la transmission glutamatergique via la voie hyperdirecte des ganglions de la base, et par conséquent favoriserait l’inhibition du thalamus qui mènera à une moindre activation du cortex moteur, et donc possiblement moins de dyskinésies. De plus, puisque l’activation des récepteurs NMDA le long de la voie nigro-striée augmente la libération de dopamine dans le striatum, il est possible qu’un effet antiparkinsonien soit également obtenu. L’objectif de cette étude est de caractériser les potentiels anti-dyskinétique, antipsychotique et antiparkinsonien de l’inhibition sélective du transporteur de la glycine 1 (GlyT1) chez deux modèles animaux de la MP. Le chapitre 1 décrit le développement et la validation d’une nouvelle méthode de détection pour quantifier les niveaux plasmatiques du bitopertin, un inhibiteur du GlyT1. Le chapitre 2 détermine le profil pharmacocinétique du bitopertin chez le rat, à la suite d’une administration sous-cutanée. Le chapitre 3 évalue l’effet du bitopertin sur la dyskinésie et le parkinsonisme chez le rat hémi-parkinsonien, montrant une amélioration significative de la dyskinésie et du parkinsonisme. Le chapitre 4 évalue l’effet de l’ALX-5407, un inhibiteur du GlyT1, sur la dyskinésie et les comportements de types psychotiques chez le ouistiti lésé au 1-méthyl-4-phényl-1,2,3,6-tétrahydropyridine (MPTP), démontrant une amélioration de la sévérité globale de la dyskinésie, des comportements de type psychose et du parkinsonisme. Dans l’ensemble, ces résultats fournissent des données convaincantes pour soutenir le potentiel thérapeutique de l’inhibition de GlyT1. De plus, le bitopertin a fait l’objet d’essais cliniques approfondies pour le traitement de la schizophrénie, et a présenté un profil de sécurité et de tolérance bien documenté, ce qui en fait un candidat attrayant pour une nouvelle étude clinique dans le traitement de la MP. / Parkinson's disease (PD) is a degenerative disorder of the central nervous system that primarily affects older people. Its main treatment is L-3,4-dihydroxyphenylalanine (L-DOPA), which unfortunately causes disabling problems such as dyskinesias and psychosis following chronic administration. Few treatments are available to effectively reduce these complications, and some interfere with the therapeutic effect of L-DOPA, while others induce potentially life-threatening side effects. It is therefore crucial to discover new therapeutic targets. Clinical and preclinical studies have shown that the glycine site of the N-methyl-D-aspartate (NMDA) receptor is a promising therapeutic target for motor problems in PD. Indeed, this may increase glutamatergic transmission via the hyperdirect pathway of the basal ganglia, and consequently promote inhibition of the thalamus, which will lead to minimal activation of the motor cortex, and therefore possibly less dyskinesia. Additionally, since activation of NMDA receptors along the nigrostriatal pathway increases dopamine release in the striatum, it is possible that an antiparkinsonian effect is also achieved. The objective of this study is to characterize the anti-dyskinetic, antipsychotic and antiparkinsonian potentials of selective inhibition of glycine transporter 1 (GlyT1) in two animal models of PD. Chapter 1 describes the development and validation of a new detection method to quantify plasma levels of bitopertin, a GlyT1 inhibitor. Chapter 2 determines the pharmacokinetic profile of bitopertin in rats, following subcutaneous administration. Chapter 3 evaluates the effect of bitopertin on dyskinesia and parkinsonism in hemi-parkinsonian rats, showing a significant improvement in dyskinesia and parkinsonism. Chapter 4 evaluates the effect of ALX-5407, a GlyT1 inhibitor, on dyskinesia and psychotic-like behaviours in marmosets injured with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), demonstrating an improvement in the overall severity of dyskinesia, psychosis-like behaviours, and parkinsonism. Taken together, these results provide compelling data to support the therapeutic potential of GlyT1 inhibition. Additionally, bitopertin has been extensively tested in clinical trials for the treatment of schizophrenia, and has demonstrated a well-documented safety and tolerability profile, making it an attractive candidate for further clinical study in the treatment of the PD.