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Serotonin was first discovered in the late 1940s as a vasotonic factor and is now considered a principal neurotransmitter in the nervous system. 5-HT6 receptors are one of the most recently identified members of the serotonin receptor family which consists of seven classes (5-HT1-5-HT7). 5-HT6 receptors are G-protein coupled, positively coupled to an adenylate cyclase second messenger system and are primarily found in the central nervous system (CNS). The exact functional role of 5-HT6 receptors has not been determined, but is implicated to have possible involvement in certain neuropsychiatric disorders and cognition. To investigate the functional role of these receptors, it is useful to identify 5-HT6 selective ligands as pharmacological tools. Our laboratory identified one of the first 5-HT6 receptor antagonists: the arylsulfonamide MS-245 (14a). It has been assumed that a sulfonyl (i.e., SO2) moiety is important for the binding of arylsulfonamides at 5-HT6 receptors. We now have identified benzyl analog 33 (R=H) as a single example of a non-sulfonyl analog that retains affinity. This questions the importance of the SO2 group and whether an aryl moiety or other hydrophobic groups (of equal or greater hydrophibicity) is required for binding. The purpose of the present investigation was to determine if the SO2, and the aryl moieties are required for high affinity binding. N1-Alkylsulfonyl- 78, and N1-benzyl-substituted tryptamines 33 were synthesized and affinities compared with their corresponding N1-benzenesulfonyl-substituted counterparts 31 at h5-HT6 receptors. None of the alkylsulfonyl or benzyl analogs displayed and/or retained the affinity of the simple benzenesulfonyl tryptamine analog (31a) (Ki = 4.1 nM). The results show that an arylsulfonyl group at the tryptamine N1 position is optimal, relative to an alkylsulfonyl group, for 5-HT6 receptor affinity. In a comparative analysis utilizing six pairs of tryptamines, it was found that there was little correspondence (r2 = 0.048) between the 5-HT6 receptor affinities of the examined benzyl and benzenesulfonyl pairs. Current findings indicate that an aryl (or substituted aryl)sulfonyl (rather than benzyl) moiety is optimal for high affinity binding, and further suggest that N1-benzenesulfonyl- and their corresponding N1-benzyltryptamine counterparts bind in a different fashion.

Vendula Dvořáčková Attitudes of patients toward antidepressant medication Master's thesis Charles University in Prague, the Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Pharmacy Background: The master's thesis deals with evaluation of attitudes of inpatients in the psychiatric clinic of Military University Hospital Prague. The main task was to clarify the relation between therapy attitude and the prescribed medication, diagnosis and sociodemographic characteristics. Methods: The data were collected using the Drug Attitude Inventory questionnaire (Czech version by Masopust) where sum of negative and positive answers was used to determine the patient's general attitude. Patients' characteristics were acquired from a data-entry form, specific medication from the medical records. Results: In the observed group women seemed to have a more positive attitude toward the treatment compared to men, similarly to people with a higher level of education and patients between 31 - 40 years of age in comparison with other age groups. The most positive responses were observed in patients who were prescribed agomelatine, trazodone and paroxetine. People diagnosed with personal disorders or affective bipolar disorder inclined to positive answers as well, on the other hand most negative...

Chez un patient épileptique, aucun examen ne permet la délimitation exacte de la zone épileptogène (ZE) qui est définie par la zone corticale nécessaire à la genèse des crises. Dans les épilepsies du lobe temporal (ELT), près d’un tiers des patients ne sont pas libres de crises après la chirurgie en dépit d’un bilan préopératoire concluant. La tomographie par émission de positons (TEP) au [18F]MPPF permet la mise en évidence de zones d’hypofixation qui sont, à l’échelle du groupe, corrélées à l’épileptogénicité du parenchyme cérébral. Afin d’évaluer la validité de la TEP au [18F]MPPF pour identifier la ZE au plan individuel, tout d'abord nous avons comparé l’analyse visuelle et statistique par SPM de la TEP au [18F]FDG à la TEP au [18F]MPPF en termes de sensibilité et de spécificité chez 42 patients souffrant d’une ELT en cours de bilan préchirurgical. Dans une seconde étude nous avons développé une méthode d’analyse statistique d’un index d’asymétrie (IA) de la fixation du [18F]MPPF [BPND] et comparé les rendements de cette nouvelle approche à l’analyse standard SPM des images TEP en utilisant deux seuils statistiques différents (p< 0,05, corrigé au niveau du voxel et p< 0,05, corrigé au niveau du cluster) chez 24 patients opérés et guéris de leur ELT. Dans une troisième étude nous avons évalué, au niveau du groupe, l’influence d’un état dépressif sur le BPND du [18F]MPPF chez 24 patients souffrant d’une ELT. Ces trois études ont permis les conclusions suivantes : i) dans des conditions d’analyse identiques, La TEP au [18F]MPPF est supérieure au [18F]FDG pour identifier le lobe épileptogène chez des patients souffrant d’une ELT, ii) L’analyse de l’IA, avec un seuil à p< 0,05 corrigé au niveau du cluster, est la meilleure technique d’analyse de la TEP au [18F]MPPF et permet l’identification de la ZE avec une sensibilité de 96% et une spécificité de 88% dans l’ELT, iii) A l’échelle du groupe, un état dépressif est responsable d’une augmentation du BPND du [18F]MPPF dans les noyaux du raphé et l’insula controlatérale à la ZE. / In patients suffering from epilepsy, no neuroimaging method has proved able to delineate the epileptogenic zone (EZ), which is defined by the area of cortex required to generate the epileptic seizures. About one third of patient suffering from temporal lobe epilepsies (TLE) are not seizure free after surgery after removal of the cortical area supposed to included the EZ according to the presurgical evaluation. Data from previous studies carried out in our departement suggested that decreases of the [18F]MPPF binding potential (BPND) correlated, at the group level, with cortical epileptogenicity. Our aim was to validate the relevance of [18F]MPPF PET at the individual level for identifying the EZ in TLE. In a first study, the [18F]MPPF PET of 42 patients suffering from TLE were visually and statistically analyzed and compared with [18F]FDG PET, which were performed in the same group of patients during their presurgical evaluation. In a second study, we developed a voxel based analysis of asymmetry index (AI) of [18F]MPPF binding and compared the sensibility and specificity of this method to those of conventional SPM analysis of [18F]MPPF PET data. This second study was carried out in 24 patients, who have been operated and remained seizure-free after surgery. Two statistical thresholds (p< 0.05 corrected at the voxel level and p< 0.05 corrected at the cluster level) were used for each method. In a last study, the correlation between the depressive symptoms and the BPND of [18F]MPPF was studied in 24 patients suffering from TLE. These three studies lead to the following conclusions: i) [18F]MPPF PET is more performant than [18F]FDG PET for identifying the epileptogenic lobe in patients suffering from TLE, ii) AI analysis with a statistical threshold of p< 0.05 corrected at the cluster is the method of analysis of [18F]MPPF PET that allowed EZ identification with the best sensitivity [96%] and specificity [88%] in TLE, iii) at the group level, depressive symptoms positively correlate with an increase of the BPND of [18F]MPPF BPND within the raphe nuclei and the insula controlateral to the EZ.

A patogenia da hiponatremia decorrente do uso da Fluoxetina em pacientes idosos não está bem definida. Este achado tem sido atribuído a uma secreção inapropriada do Hormônio Antidiurétido (HAD), embora ainda não tenha sido evidenciado um aumento dos níveis plasmático deste hormônio nestes pacientes. Desta forma, este trabalho visa investigar o efeito da Fluoxetina sobre o rim e mais especificamente se ela teria um efeito direto sobre o Ducto Coletor Medular Interno (DCMI) de ratos normais: 1) Estudos in vivo- 10 ratos foram suplementados com aplicações intraperitoniais diárias de 10mg/kg de Fluoxetina. Após 10 dias os animais foram sacrificados e o sangue e os rins foram coletados para posterior análise. 2) Estudos in vitro- a) estudos com a técnica de Imunoblotting para avaliar a expressão da proteína da Aquaporina 2 (AQP2) em ratos suplementados e em suspensão de túbulos de DCMI de 10 ratos normais incubados com 10-7M de Fluoxetina por 30 min. b) estudos com microperfusão de segmentos isolados do nefron- a permeabilidade osmótica à água (Pf, mm./sec) foi determinada em DCMI perfundidos de ratos normais(n=6) com a técnica standart, na presença de10-7M de Fluoxetina. Resultados: 1) Os estudos in vivo mostraram que o peso caiu de 179±1,28g para 158±1,15g (p<0,0001), o Na plasmático caiu de 139,3±0,78mEq/l para 134,9±0,5mEq/l (p<0,0001) e não houve alterações do K e do HAD plasmáticos. 2) Os estudos in vitro-a) a análise densitométrica dos ensaios com imunoblotting mostraram um aumento da expressão da proteína da AQP2 de 40%, ambos, em ratos suplementados (cont-99,6± 5,2 vs Fx 145,6±16,9, p< 0,05) e em frações de membrana da suspensão de túbulos incubados com Fluoxetina (cont-100,0±3,5.vs 143,0±2,0, p<0,01). b) A Fluoxetina aumentou a Pf nos DCMI, na ausência de HAD de 7,24±2,07 para Fx- 15,77±3,25 (p<0,01). Em resumo, nossos dados revelaram que a Fluoxetina determinou uma diminuição do peso corporal e do nível plasmático de Na sem alterar os níveis plasmáticos de K e HAD e ocasionou um aumento da expressão da proteína da AQP2 e um aumento da permeabilidade à água nos DCMI, levando-nos à conclusão de que o efeito direto da Fluoxetina no DCMI, aumentando a reabsorção de água, pode ser responsável pela hiponatremia encontrada nos pacientes idosos com depressão que fazem uso desta droga. / The pathogenesis of the hyponatremia after Fluoxetine(Fx) supply in elderly is not well understood. This event has been attributed to an inappropriate antidiuretic hormone secretion although the vasopressin enhanced plasma level has not been demonstrated yet in these pacients. Thus, this experiment was designed to investigate the effect of Fx on the kidney and more specifically if it would have a direct effect in the inner medullary collecting duct (IMCD) from normal rats: 1) in vivo study- 10 rats were supplied daily with i.p. injections of Fx 10 mg/kg. After five days, the rats were sacrificed and blood and kidneys were collected. 2) in vitro studya) Immunobloting studies for AQP2 protein expression, in IMCD from supplied rats and in IMCD tubules suspension from 10 normal rats incubated with mm./sec) Fx. by 30 min. b) Microperfusion studies- the osmotic water permeability (Pf, mm./sec) was determined in normal rats IMCD(n=6) isolated and perfused by the standart methods.Fx (10-7M) was added to the bath fluid. Results: In vivo study showed that the weight decreased from 179±1.28g to 158±1.5g(p<0.0001); the Na+ plasma level decreased from 139.3±0.78mEq/l to 134.9±0.5mEq/l(p<0.0001), the K+ and the ADH plasma level remained unchanged. In vitro study- a) the densitometric analysis of the immunobloting essays showed an increase in AQP2 protein abundance of about about 40%, both, in supplied rats (cont-99.6± 5.2 vs Fx 145.6±16.9, p< 0.05), and in membrane fraction extracted from IMCD tubule suspension incubated with Fx ( cont-100.0±3.5.vs 143.0±2.0,p<0.01). b) Fx increased the Pf in IMCD in absence of vasopressin from the control period- 7.24±2.07 to Fx- 15.77±3.25 (p<0.01). In summary, our data revealed that, after Fx, weight, and plasma Na+ level decreased, the plasma K+ and ADH levels remained unchanged, whereas the AQP2 protein abundance and the water absorption in IMCD increased, leading us to conclude that the direct effect of Fx in the IMCD, could account for the hyponatremia produced by this drug in depressed elderly.

Não disponível / Not available

A depressão é o mais comum dos distúrbios afetivos. Afeta ao menos 10% da população idosa do Brasil. Nos idosos, alguns fatores ligados ao metabolismo parecem estar bastante relacionados a esse transtorno, como uma menor concentração de noradrenalina e serotonina (5-HT) e uma maior atividade da monoaminooxidase em relação a adultos jovens. Os inibidores seletivos da recaptação da serotonina (ISRS), principalmente a sertralina, são a primeira opção no tratamento da fase aguda e manutenção dos episódios depressivos em idosos. As plaquetas vêm sendo amplamente utilizadas como modelo para estudar na periferia alterações que ocorrem no sistema nervoso central. A 5-HT apesar de ser primordialmente expressa no cérebro, também pode ser encontrada em plaquetas. Este neurotransmissor está envolvido em inúmeros aspectos do funcionamento normal do cérebro desde a regulação do humor até a regulação hormonal. A deficiência nos níveis de 5-HT pode estar intimamente ligada a alguma anormalidade na atividade da glicogênio sintase quinase 3B(GSK3B). Esta enzima exerce funções no metabolismo celular que vão desde sobrevivência celular, metabolismo e processamento de proteínas, até processos cognitivos. A atividade da GSK3B é estreitamente regulada pela fosforilação. Fosforilação no sítio ser9 inativa a enzima, enquanto que a desfosforilação neste mesmo sítio ativa a enzima. Diversos estudos têm mostrado que a forma inativa da enzima exerce um efeito neuroprotetor. O objetivo do presente estudo foi verificar a influência do tratamento com sertralina, em pacientes idosos com diagnóstico de depressão maior, sobre a 5- HT e GSK3B após 3 e 12 meses de tratamento. A quantificação da 5-HT foi realizada por HPLC e da GSK3B plaquetária, pelos métodos de ELISA e blotting, que se revelaram equivalentes. Após um ano de tratamento encontramos uma diminuição da 5-HT plaquetária nos pacientes com depressão maior com relação aos níveis basais, bem como um aumento da forma total da enzima GSK3B (GSKT), uma diminuição da forma fosforilada (pGSK) e da razão entre pGSK e GSKT (rGSK). Quando comparados os níveis de GSK3B de pacientes tratados por um ano e controles, observamos uma maior expressão de GSKT em pacientes; enquanto a pGSK e rGSK se mostraram equivalentes. Pudemos observar, portanto, uma modulação da 5-HT e da GSK3B pelo uso de sertralina. Essa modulação pode indicar que a ação antidepressiva deste fármaco pode estar associada a essas vias de sinalização / Depression is the most common affective disorders. It affects at least 10% of the elderly population of Brazil. In the elderly, some factors related to metabolism appear to be closely related to this disorder, such as lower concentration of noradrenaline and serotonin (5-HT) and increased monoamine oxidase activity in relation to young adults. The selective serotonin reuptake inhibitors (SSRI), especially sertraline are the first choice in treating acute and maintenance of depressive episodes in the elderly. Platelets have been widely used as a model to study in peripheral changes that occur in Central Nervous System. Although 5-HT is primarily expressed in the brain, it can also be found in platelets. This neurotransmitter is involved in numerous aspects of normal brain function since the regulation of mood to the hormonal regulation. A deficiency in 5-HT levels may be closely related to an abnormality in glycogen synthase kinase 3B (GSK3B) activity. This enzyme plays several functions in cell metabolism, ranging from cell survival, metabolism and protein processing, to cognitive processes. The GSK3B activity is tightly regulated by phosphorylation. Phosphorylation on Ser9 site inactives the enzyme, whereas dephosphorylation in the same site actives the enzyme. Several studies have shown that the inactive form of the enzyme plays a neuroprotective effect. The objective of this study was to investigate the influence of sertraline in elderly patients diagnosed with major depression, on platelet 5-HT and GSK3B after 3 and 12 months of treatment. Quantification of 5-HT was performed by HPLC and GSK3B by ELISA and western blotting. The methods for platelet GSK3B determination showed to be equivalent. After one year of treatment we found a decrease of platelet 5-HT in patients with major depression relative to their baseline levels, as well as an increase in the total form of GSK3B enzyme (GSKT), a decrease in phosphorylated form (pGSK) and the ratio between pGSK and GSKT (rGSK). Comparing the levels of GSK3B of patients with one year of treatment and controls, we found a higher GSKT expression in patients; while pGSK and rGSK showed to be equivalent. Therefore we observed a modulation of 5-HT and GSK3B by sertraline. This modulation may indicate that the antidepressant action of this drug may be associated with these signaling pathways

Made available in DSpace on 2016-08-10T10:38:40Z (GMT). No. of bitstreams: 1 FERNANDA APARECIDA VARGAS DE BRITO E ALVES.pdf: 1009586 bytes, checksum: 8dc12edf912fed637ebefe39ffdd52d4 (MD5) Previous issue date: 2012-06-30 / Introduction: Fibromyalgia is a syndrome characterized by widespread chronic pain. The syndrome is chronic with dubious possibility of healing. The prevalence in the world population varies from 0,66 to 4,4 %. It is believed that fibromyalgia is the result of abnormal changes in sensory processing of pain. In this context, are inserted gene polymorphisms T102C gene HTR2A serotonin receptor. The HTR2A gene T102C polymorphism is the presence of a thymine (T) or cytosine (C), defined by a transition from T to C at nucleotide position 102. It is a silent polymorphism receptor gene HTR2A, which determine the different levels of gene expression. Objectives: To determine and compare the allele frequency and genotype of the T102C polymorphism of the serotonin receptor gene HTR2A in a group of 48 women diagnosed with fibromyalgia and 50 healthy controls. Methodology: For this we used the PCR- RFLP , from DNA extracted from peripheral blood samples obtained from control and testing. The comparison of allele and genotype frequencies was performed by Chi -square test. Results: The results showed allele frequencies obtained for both groups were: T (46,9%) and C (53,1%). The TT genotype frequencies were found (22,9%), TC (47,9%) and CC (29,2%) for patients with fibromyalgia and TT (16%), TC (70%) and CC (14%) for controls. Conclusions: The FMS is composed of multiple characteristics that reflect a diversity of causes. Our results showed a significantly higher frequency for the CC genotype in patients with FMS, partially explaining the reduced serotoninergic response observed in such patients. / Introdução: A Fibromialgia é uma síndrome reumática caracterizada por dor difusa e crônica. A síndrome é crônica com duvidosa possibilidade de cura. A prevalência na população mundial varia de 0,66 a 4,4%. Acredita-se que a fibromialgia seja o resultado de mudanças anormais no processamento sensorial da dor. Neste contexto, inserem-se os polimorfismos do gene T102C do gene do receptor de serotonina HTR2A. O polimorfismo T102C do gene HTR2A consiste na presença de uma timina (T) ou citosina (C), definida por uma transição de um T para C na posição nucleotídica 102. Trata-se de um polimorfismo silencioso do gene do receptor HTR2A, que determinam níveis de expressão gênica diferentes. Objetivos: Determinar e comparar a freqüência alélica e genotípica do polimorfismo T102C do gene do receptor de serotonina HTR2A em um grupo de 48 mulheres diagnosticadas com fibromialgia e 50 controles saudáveis. Metodologia: Para isso foi utilizada a técnica de PCR-RFLP, a partir de DNA extraído de amostras de sangue periférico obtidas do grupo controle e testes. A comparação das freqüências alélicas e genotípicas foi feita por meio de teste Chi-quadrado. Resultados: Os resultados demonstraram as freqüências alélicas obtidas para os dois grupos foram: T (46,9%) e C (53,1%). As freqüências genotípicas encontradas foram TT (22,9%); TC (47,9%) e CC (29,2%) para os pacientes com fibromialgia e TT (16%); TC (70%) e CC (14%) para os controles. Conclusões: A SFM é composta por múltiplas características que refletem em uma diversidade de causas. Nossos resultados demonstraram que o genótipo CC foi significativamente mais comum nas pacientes com a SFM, justificando parcialmente a menor resposta serotononérgica observada nesse grupo.

Made available in DSpace on 2016-08-10T10:38:51Z (GMT). No. of bitstreams: 1 PAULA APARECIDA BORGES PERES.pdf: 1092863 bytes, checksum: 6b1ba024090a288ed778814bb2668c7f (MD5) Previous issue date: 2012-08-31 / Despite its obscure aetiopathology, fibromyalgia is defined by diffuse musculoskeletal pain and not joint, and heightened sensitivity to palpation of certain muscle points, mainly affecting women, in a ratio of 6 to 10 women for every man. Several studies have demonstrated the role of polymorphisms of genes serotonergic, dopaminergic and catecholaminergic in the etiology of fibromyalgia. Thus, genetic factors may be determinants in the pathogenesis of fibromyalgia and some environmental factors may trigger fibromyalgia in genetically predisposed individuals. In this context, it seems that the gene polymorphism T102C serotonin receptor (5-HT2A) is relevant in susceptibility to fibromyalgia. The objective of this study was to perform a metaanalysis in order to investigate the association between polymorphism of the serotonin receptor gene (5-HT2A), the T102C SNP in susceptibility to fibromyalgia. Five studies, between the years 1999 to 2011, about 5-HT2AT102C polymorphism in fibromyalgia were selected and used for making a meta-analysis. The epidemiological profile of fibromyalgia patients revealed a mean age of 46.7 (+ 5.9) years, with extremes ranging from 21 to 77 years. The proportion between genders showed a difference of approximately 7 women for every man diagnosed fibromyalgia. The average time in which patients suffering from fibromyalgia syndrome is 7.4 (+ 2.9) years. Allele frequencies for T and C, the gene for 5- HT2AT102C were, respectively, for patients: 337 (43.1%) and 445 (56.9%) and for the controls: 362 (51.6%) and 340 (48.4%), indicating a predominance of the C allele in patients with fibromyalgia (p=0.0013). When evaluating the genotypic frequencies, we found: 73 (18.7%) TT, 191 (48.8%) and TC 127 (32.5%) CC. The control group: 98 (27.9%) TT, 166 (47.3%) and TC 87 (24.8%) CC. The CC genotype appears more frequently in the patients fibromyalgia patients (p=0.0046). A meta-analysis generated a universe of simultaneous evaluation of 742 individuals (391 fibromyalgia patients and 351 controls). The applied tests indicated no significant differences between the case and control groups. Thus, the result of the meta-analysis suggests no correlation between polymorphism in question and susceptibility to fibromyalgia. We suggest the use of a broad panel of SNPs with the intention of increasing the chances of finding an association between genetic polymorphisms and susceptibility to fibromyalgia. / Apesar de sua etiopatologia obscura, a fibromialgia é definida por dores musculoesqueléticas difusas e não articulares e sensibilidade a palpação exacerbada em determinados pontos musculares, afetando principalmente mulheres, numa proporção de 6 a 10 mulheres para cada homem. Vários estudos têm demonstrado o papel relevante dos polimorfismos de genes serotoninérgicos, dopaminérgicos e catecolaminérgicos na etiologia da fibromialgia. Desta forma, fatores genéticos podem ser determinantes na patogênese da fibromialgia e alguns fatores ambientais podem desencadear a fibromialgia em indivíduos geneticamente predispostos. Neste contexto, parece que o polimorfismo T102C do gene do receptor da serotonina (5-HT2A) pode ser relevante na suscetibilidade à fibromialgia. Assim, o objetivo do presente trabalho foi o de realizar uma meta-análise com o intuito de investigar a associação entre o polimorfismo do gene do receptor da serotonina (5- HT2A), no SNP T102C, na suscetibilidade à fibromialgia. Cinco estudos, entre os anos de 1999 a 2011, sobre o polimorfismo 5-HT2AT102C em fibromialgia foram selecionados e utilizados para a confecção de uma meta-análise. O perfil epidemiológico dos pacientes fibromiálgicos revelou uma idade média de 46,7 (+ 5,9) anos, com os extremos variando de 21 a 77 anos. Adiconalmente, a proporção entre gêneros apontou uma diferença de aproximadamente 7 mulheres com fibromialgia para cada homem diagnosticado. O tempo médio em que os pacientes sofrem da síndrome fibromiálgica é de 7,4 (+ 2,9) anos. As frequências alélicas para T e C, para o gene 5-HT2AT102C, foram, respectivamente, para os pacientes: 337 (43,1%) e 445 (56,9%) e para os controles: 362 (51,6%) e 340 (48,4%), indicando um predomínio do alelo C em pacientes com fibromialgia (p=0,0013). Ao avaliar as frequências genotípicas, encontrou-se: 73 (18,7%) TT, 191 (48,8%) TC e 127 (32,5%) CC. No grupo controle foram: 98 (27,9%) TT, 166 (47,3%) TC e 87 (24,8%) CC. O genótipo CC aparece em maior frequência no grupo dos pacientes fibromiálgico (p=0,0046). A meta-análise gerou um universo de avaliação simultânea de 742 indivíduos (391 pacientes com fibromialgia e 351 controles). Os testes aplicados não indicaram diferenças significativas entre os grupos caso e controle. Assim, o resultado da meta-análise sugere ausência de correlação entre o polimorfismo em questão e a suscetibilidade à fibromialgia. Sugerimos a utilização de um amplo painel de SNPs com a intenção de aumentar as chances de se encontrar associação entre polimorfismos gênicos e suscetibilidade à fibromialgia.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-27T15:36:18Z No. of bitstreams: 1 VANDREZA CARDOSO BORTOLOTTO.pdf: 2120802 bytes, checksum: d9c6e128c892e469fe3f24a3ebad9f86 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-27T15:36:32Z (GMT) No. of bitstreams: 1 VANDREZA CARDOSO BORTOLOTTO.pdf: 2120802 bytes, checksum: d9c6e128c892e469fe3f24a3ebad9f86 (MD5) / Made available in DSpace on 2018-09-27T15:36:32Z (GMT). No. of bitstreams: 1 VANDREZA CARDOSO BORTOLOTTO.pdf: 2120802 bytes, checksum: d9c6e128c892e469fe3f24a3ebad9f86 (MD5) Previous issue date: 2017-07-17 / A glândula tireoide é uma das maiores glândulas do corpo, responsável pela produção de triiodotironina (T3) e tiroxina (T4), hormônios responsáveis pela homeostase do organismo. A redução na produção destes hormônios leva a um quadro de hipotireoidismo. O hipotireoidismo é uma desordem endócrina, mais prevalente no sexo feminino, e que pode causar uma série de alterações comportamentais e neurológicas, dentre elas a depressão. O flavonoide crisina, presente no maracujá do mato, própolis e mel de abelha, vem sendo estudado a alguns anos, sendo relatados seus efeitos antioxidantes, anticancerígenos, antihiperglicêmicos, ansiolíticos, e atualmente tem-se demonstrado sua atividade antidepressiva. O objetivo deste estudo foi investigar a ação terapêutica da crisina em modelo tipo depressivo induzido pelo hipotireoidismo em camundongos fêmeas C57BL/6 adultas. Primeiramernte os animais foram divididos em dois grandes grupos (n=20): controle e hipotireoidismo. O hipotireoidismo foi induzido por exposição contínua ao fármaco antitireoideo metimazol (MTZ) 0,1% + 0,475% de sucralose, durante 31 dias na água. No 31º dia foi retirado sangue da veia caudal e determinado os níveis de T3 e T4. Após os animais foram separados em quatro grupos (n=10): controle, hipotireoidismo, crisina, hipotireoidismo + crisina. A crisina (20mg/kg) foi administrada diariamente por 28 dias, via oral. Ao final do tratamento, os animais passaram por testes comportamentais de campo aberto (TCA), nado forçado (TNF) e suspensão de cauda (TSC), após realizou-se eutanásia nos animais, e coletou-se o sangue por punção cardíaca para análise bioquímica de T3 e T4, e retirou-se as estruturas cerebrais hipocampo e córtex pré frontal, para análises neuroquímicas de serotonina (5-HT), dopamina (DA), norepinefrina (NA). Nossos resultados demonstraram que os animais com hipotireoidismo apresentaram um aumento no tempo de imobilidade nos testes de TNF e TSC e a crisina foi capaz de reverter este tempo em ambos os testes. Demonstrou-se também que a crisina foi capaz de restaurar os níveis de neurotransmissores: 5-HT em ambas estruturas cerebrais e DA no hipocampo dos animais com hipotireoidismo, corroborando com os resultados dos testes comportamentais, nos quais o TNF está relacionado com o sistema serotoninérgico e o TSC com o sistema dopaminérgico. Em conclusão, nossos resultados demonstram pela primeira vez que a crisina é capaz de reverter o estado tipo depressivo induzido pelo hipotireoidismo, possivelmente por normalizar os níveis de 5-HT e DA. / The thyroid gland is one of the largest glands in the body, it produces triiodothyronine (T3) and thyroxine (T4), these hormones are responsible for body homeostasis. The reduction in the production of these hormones leads to hypothyroidism. The hypothyroidism is an endocrine disorder, more prevalent in females, which can cause a number of behavioral and neurological changes, including depression. The chrysin flavonoid present in the passion fruit of the bush, propolis and bee honey, has been studied for some years, being reported your antioxidant effect, anticancer, antihyperglycemic, anxiolytic, and currently your antidepressant activity was demonstrated. The objective of this study was to investigate the therapeutic action of chrysin in a model of like-depression induced by hypothyroidism in adult C57BL/6 female mice. First, the animals were divided into two groups (n=20): control and hypothyroidism. Hypothyroidism was induced by continuous exposure to the antithyroid drug methimazole (MTZ) 0.1% + 0.475% sucralose for 31 days on water. On the 31st day blood was drawn from the caudal vein and T3 and T4 levels were determined. After the animals were separated into four groups (n=10): control, hypothyroidism, chrysin, hypothyroidism + chrysin. The treatment of chrysin (20mg/kg) was administered daily for 28 days, orally. At the end of treatment the animals they passed for behavioral tests of open field test (OFT), forced swimming test (FST) and tail suspension test (TST), performed euthanasia in the animals, and collected the blood by cardiac puncture for biochemical analyze of T3 and T4, and the hippocampus and prefrontal cortex brain structures were removed for neurochemical analyzes of serotonin (5-HT), dopamine (DA), norepinephrine (NA). Our results demonstrated that animals with hypothyroidism showed an increase in the time of immobility in the tests of FST and TST and the chrysin was able to reverse this time in both tests. It was also demonstrated that the chrysin was able to restore the levels of neurotransmitters: 5-HT in both structures cerebral and DA in the hippocampus of animals with hypothyroidism, corroborating with the results of behavioral tests, in which FST is related to the serotonergic system and the TST with the dopaminergic system. In conclusion, our results demonstrate for the first time that chrysin is able of reversing the depressive-induced state induced by hypothyroidism, possibly by normalizing 5-HT and DA levels.