Bien que l’effet psychotrope des antidépresseurs soit bien connu, afin de corriger les conséquences du stress et de renforcer la confiance en soi, de nombreux autres effets pharmacologiques, notamment périphériques, doivent encore être approfondis. Les antidépresseurs inhibiteurs de la recapture de la sérotonine (ISRS) peuvent avoir un effet bénéfique sur la performance physique en participant à une réparation et à une croissance plus rapides des muscles. Il a récemment été démontré que la sérotonine était impliquée dans la récupération de la force musculaire chez un modèle murin de myopathie de Duchenne (Gurel et al., 2015). Les antidépresseurs tels que les inhibiteurs sélectifs de la recapture de la sérotonine (ISRS) sont largement utilisés pour traiter divers troubles de la santé mentale, tels que la dépression modérée à sévère et l’anxiété. Les deux symptômes contribuent à l’insomnie, à la perte d’appétit, au manque de motivation et à une fatigue physique accrue. Ces symptômes peuvent nuire aux performances physiques des athlètes, en particulier de ceux qui développent des habiletés et des techniques spécifiques à un sport, reçoivent des volumes d’entraînement plus importants à différentes intensités et participent à des compétitions plus fréquentes. Par conséquent, les athlètes peuvent utiliser des médicaments qui renforcent la motivation et / ou améliorent la condition physique générale en réduisant les symptômes dépressifs. L'utilisation d'antidépresseurs n'est pas encore interdite dans les sports d'élite. Des rapports récents sur le dopage associé aux ISRS montrent une tendance croissante de son utilisation chez les athlètes en bonne santé. La consommation d'antidépresseurs chez les athlètes a augmenté dans différents sports au cours de la dernière décennie, notamment les sports d'endurance.. Notre projet doit donc permettre de caractériser les conséquences d'un traitement chronique par ISRS sur les performances physiques chez la souris et de mettre en évidence le ou les mécanismes impliqués, en particulier la variation du shunt métabolique sérotonine / kynurénine, ainsi que les modifications de biomarqueurs, variations potentiellement utilisables chez l'homme dans la lutte contre le dopage.Nous aimerions élucider notre travail de recherche dans les articles suivants:Article 1: Nous avons étudié les effets de l'exercice et de la fluoxétine seuls ou en association avec un traitement prolongé à la fluoxétine (18 mg / kg / jour) et un exercice physique d'endurance (six semaines) chez la souris mâle BalbC / j, sur tapis roulant. Nous avons ensuite évalué l'activité neurocomportementale, les marqueurs musculaires du stress oxydatif et les modifications du métabolisme du tryptophane dans les tissus plasmatiques, musculaires et cérébraux des souris BalbC / J. En général, nous nous sommes concentrés sur la vitesse aérobie la plus élevée, le temps d’endurance jusqu’à l’épuisement, la force musculaire des membres antérieurs en saisissant un mesureur de force, des tests neurocomportementaux tels que le test en champ ouvert et élevé et le labyrinthe, l’activité enzymatique mitochondriale (activité du citrate synthase et du cytochrome C oxydase) dans le muscle gastrocnémien. , marqueur de stress oxydant tel que le test DHE (Dihydroéthidium) et DCF-DA (Dichlorofluorscine diacétate).Article 2: Nous avons étudié les effets de l’exercice et de la fluoxétine seule ou les effets combinés d’un traitement prolongé à la fluoxétine (18 mg / kg / jour) et d’un exercice d’endurance physique (six semaines) chez la souris mâle BalbC / j, sur tapis roulant. / As much as the psychotropic effect of antidepressants is well known, correcting the consequences of stress and boosting self-confidence, so many other pharmacological effects, peripheral in particular, remain to be deepened. Serotonin reuptake inhibitor antidepressants (SSRIs) may have a beneficial effect on physical performance by participating in faster muscle repair and growth. It has recently been shown that serotonin was involved in the recovery of muscle strength in a mouse model of Duchenne myopathy (Gurel et al., 2015).Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely used to treat various mental health disorders, such as moderate-to-severe depression and anxiety. Both symptoms contribute to insomnia, loss of appetite, lack of motivation and increased physical fatigue. These symptoms can impair physical performances for athletes, more specifically for those who develop sport-specific skills and techniques, receive higher training volumes at various intensities, and participate in more frequent competitions. Therefore athletes may use drugs that enhance motivation and/or improve overall fitness by reducing depressive symptoms. The use of antidepressants is not yet forbidden in elite sports. Recent reports on doping associated with SSRIs show an increasing trend of its usage among healthy athletes. The antidepressants intake among athletes has increased in different sports over the last decade, especially endurance sports. The antidepressants Bupropion and Amineptine were removed from the list of banned substances.Our project must therefore make it possible to characterize the consequences of chronic treatment with SSRIs on the physical performance in mice and to highlight the mechanism (s) involved, in particular the variation of the serotonin / kynurenine metabolic shunt, as well as the modifications of biomarkers, potentially usable variations in humans in the fight against doping.We would like to elucidate our research work in the following articles:Article 1: We studied the effects of exercise and fluoxetine alone or in combination of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. Subsequently we evaluated neurobehavioral activity, muscle markers of oxidative stress, and changes in tryptophan metabolism in plasma, muscle and brain tissues in the BalbC/J mice. Generally we focused on the highest aerobic velocity, endurance time until exhaustion, forelimb muscle strength by gripping strength meter, neurobehavioral tests such as open field and elevated plus maze test, mitochondrial enzyme activity (Citrate synthase and cytochrome-C oxidase activity) in gastrocnemius muscle, oxidative stress marker such as DHE (Dihydroethidium) and DCF-DA (Dichlorofluorscine di-acetate)test.Article 2: We studied the effects of exercise and fluoxetine alone or combinative effects of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. After the mentioned exercise protocol we focused on changes in tryptophan (TRP) metabolism in plasma, muscle and brain tissues in the BalbC/J mice. To confirm the metabolomic, we also studied the KP related enzyme related genes and proteins by the modern required materials and methods. We correlated the result of article1 with the metabolites level of kynurenine pathway of tryptophan metabolism. We studied the expression of transcriptor factor PGC1α level in muscle which is induced by physical exercise(Agudelo et al., 2014). PGC1α subsequently induce the expression of kynurenine aminotransferase 1 and 2 (KAT1 and KAT2) in skeletal muscles, which convert kynurenine (KYN) to kynurenic acid (KYNA). Conversion of kynurenine to kynurenic acid decrease the level of kynurenine and quinolinic acid an NMDA receptor agonist and a neurotoxic compound.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-27T14:35:42Z No. of bitstreams: 1 MANUELA BASTOS PIEGAS.pdf: 958703 bytes, checksum: c8f6ec5dce6bda264ca299a05edc76bf (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-27T14:35:52Z (GMT) No. of bitstreams: 1 MANUELA BASTOS PIEGAS.pdf: 958703 bytes, checksum: c8f6ec5dce6bda264ca299a05edc76bf (MD5) / Made available in DSpace on 2018-09-27T14:35:52Z (GMT). No. of bitstreams: 1 MANUELA BASTOS PIEGAS.pdf: 958703 bytes, checksum: c8f6ec5dce6bda264ca299a05edc76bf (MD5) Previous issue date: 2017-07-14 / A radiação ultravioleta (UV) B no tecido epitelial estimula a síntese e liberação de mediadores pró-inflamatórios, induzindo à infiltração e ativação de neutrófilos e outras células fagocíticas. Assim, processos inflamatórios causados pela radiação UVB podem ser prejudiciais sobre diversas células do organismo, causando desde fotoenvelhecimento até imunossupressão. O triptofano (TRIP) é um aminoácido essencial, utilizado em inúmeros processos fisiológicos e metabolizado por duas vias principais, a serotoninérgica e a das quinureninas. Sendo esta última relacionada a enzima indoleamina 2,3 dioxigenase (IDO) que poderá ser induzida por processos inflamatórios aumentando o consumo de TRIP e formando metabólitos oxidativos, como o ácido quinolínico que está relacionado no processo de imunotolerância. Devido ao envolvimento da enzima IDO e seu possível alvo terapêutico, o objetivo desse trabalho foi avaliar a produção de metabólitos da via das quinureninas (VQs) em lesões auriculares de camundongos, provocadas pela exposição por 24 horas à radiação UVB frente ao inibidor da enzima IDO 1-metil triptofano (1-MT). Os experimentos foram realizados com 30 animais da linhagem C57B/6J. Após serem divididos em cinco grupos de seis animais cada, denominados: a) controle, sem exposição à radiação UVB; b) veículo, exposto a radiação UVB tratado com salina (10μL); c) expostos a radiação UVB e tratados com inibidor da enzima1-MT (0,5 μg/μl); d) expostos a radiação UVB e tratados com inibidor da enzima 1-MT (1,0 μg/μl) e grupo e) expostos a radiação UVB e tratados com inibidor da enzima 1-MT (2,0μg/μl). O tratamento com 1-MT e o veículo foram realizados topicamente antes da exposição à radiação UVB, e 24h depois da exposição, os camundongos foram eutanasiados e as orelhas totalmente extraídas para realização das dosagens específicas. O presente estudo demonstrou que o tratamento com 1-MT frente à radiação UVB em lesões auriculares de camundongos, foi eficaz em atenuar as seguintes alterações, a espessura e inflamação das orelhas irradiadas, o estresse oxidativo causado pela radiação UVB nas 7 orelhas dos camundongos. Diminuiu os níveis de fator de necrose tumoral alfa (TNF-α), interleucina 1 beta (IL-1β), interleucina 6 (IL-6), interferon gama (INF-γ), interleucina 13 (IL-13), interleucina 17 (IL-17), interleucina 10 (IL-10) e fator nuclear kappa B (NF-κB) reduzindo os níveis das citocinas inflamatórias. Aumentou os níveis de TRIP no local, diminuindo assim seus metabólitos como quinurenina (QUI), ácido quinurênico (AQUI), 3-Hidroxiquinurenina (3-HQ), ácido 3-hidroxiantranílico (3-AA), ácido antranílico (AA) e ácido quinulínico (AQ). Aumento das atividades das enzimas envolvidas na VQs, entre elas a IDO, quinurenina 3-monoxigenase (QMO), quinurenina aminotransferase (QAT) e quinureninase (QUINU). Em conclusão, esses resultados demonstram que a inibição da enzima IDO causou atenuação da inflamação, do estresse oxidativo e dos metabólitos da VQs. Além disso, sugerem que a inibição dessa enzima, seja com produtos sintéticos ou naturais podem fornecer uma nova abordagem terapêutica para o tratamento e prevenção de lesões causadas pela radiação UVB na pele. / Ultraviolet (UV) B radiation in the epithelial tissue stimulates the synthesis and release of pro-inflammatory mediators, inducing the infiltration and activation of neutrophils and other phagocytic cells. Thus, inflammatory processes caused by UVB radiation can be harmful to various cells in the body, from photoaging to immonussuppression. Tryptophan (TRYP) is an essential amino acid, used in numerous physiological processes and metabolized by two main pathways, serotoninergic and kynurenines. The latter is related to the indoleamine 2,3 dioxygenase (IDO) enzyme that can be induced by inflammatory processes increasing the consumption of TRYP and forming oxidative metabolites, such as the quinolinic acid that is related in the process of immunotolerance. Due to the involvement of the IDO enzyme and its possible therapeutic target, the objective of this work was to evaluate the production of metabolites of the kinurenins pathway (KPs) in mice ear lesions caused by 24-hour UVB exposure to the IDO enzyme inhibitor 1-methyl tryptophan (1-MT). The experiments were performed with 30 animals of the C57B / 6J lineage. After being divided into five groups of six animals called: a) control, without exposure to UVB radiation; B) vehicle, exposed to UVB radiation treated with saline (10μL); C) exposed to UVB radiation and treated with 1-MT enzyme inhibitor (0,5 μg/μl); D) exposed to UVB radiation and treated with 1-MT enzyme inhibitor (1,0 μg/μl) and group e) exposed to UVB radiation and treated with 1-MT enzyme inhibitor (2,0 μg/μl). Treatment with 1-MT and the vehicle were performed topically prior to exposure to UVB radiation, and 24 hours after exposure, the mice were euthanized and the ears fully extracted for specific dosages. The present study demonstrated that 1-MT 9 treatment against UVB radiation in mouse ear lesions was effective in attenuating the following alterations, the thickness and inflammation of the irradiated ears, the oxidative stress caused by UVB radiation in the ears of the mice. It decreased levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interferon gamma (INF-γ), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin-10 (IL-10) and nuclear factor kappa B (NF-κB), reducing levels of inflammatory cytokines. Increased TRIP levels at the site, thereby decreasing its metabolites such as kynurenine (KYN), kynurenic acid (KYNA), 3-Hydroxyquinurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), anthranilic acid (AA) e quinolinic acid (QA). Increased activities of the enzymes involved in KPs, including IDO, kynurenine 3-monoxygenase (KMO), kynurenine aminotransferase (KAT) and kynureninase (KYNU). In conclusion, these results demonstrate that inhibition of the IDO enzyme caused attenuation of inflammation, oxidative stress and metabolites of KPs. In addition, they suggest that the inhibition of this enzyme, either with synthetic or natural products may provide a new therapeutic approach for the treatment and prevention of injuries caused by UVB radiation on the skin.