Influência do dimorfismo sexual na resposta ao tratamento com fluoxetina em ratos no nado forçado repetido: contribuição do metabolismo da serotonina

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2015.Diferenças sexuais são descritas na resposta a antidepressivos no teste do nado forçado, em ratos. O teste do nado forçado repetido (TNF-r) avalia os efeitos agudos e crônicos do tratamento com antidepressivos no mesmo grupo de animais. O TNF-r consiste de uma sessão de nado de 15minutos (pré-teste) seguida de sessões de 5minutos no primeiro (teste), sétimo (reteste 1) e décimo quarto (reteste 2) dias após o pré-teste. Em ratos machos, a repetição induz um aumento do tempo de imobilidade. Este efeito é contraposto pelo tratamento com antidepressivos. O objetivo deste estudo foi comparar os efeitos do tratamento com fluoxetina (FLX) em ratos machos e fêmeas expostos ao TNF-r. Para tal, ratos machos e fêmeas foram treinados a ingerir uma solução de sacarose 10% por 7dias. Após este período, os grupos foram designados. Os machos receberam sacarose 10% (vei) ou FLX 2,5mg/Kg. As fêmeas receberam vei, FLX 1mg/Kg, FLX 2,5mg/Kg ou FLX 5mg/Kg. O tratamento teve duração de 14 dias. A repetição do teste falhou em aumentar significativamente o tempo de imobilidade nos machos, e também, em fêmeas. Estes efeitos podem ser atribuídos as propriedades apetitivas da sacarose. O tempo de imobilidade nas fêmeas também não foi afetado pela repe. O tratamento crônico com FLX reduziu o tempo de imobilidade nos machos, mas não nas fêmeas. Considerando estes resultados, sugerimos que poderia existir um dimorfismo sexual no sistema serotoninérgico destes animais. Para investigar essa hipótese, os animais foram decapitados sob anestesia e regiões do encéfalo foram dissecadas. Estas regiões foram incubadas in vitro com veículo ou serotonina (5-HT) e analisadas por cromatografia líquida de alta eficiência (CLAE) com detecção eletroquímica. Encontramos que, no hipocampo, as concentrações de 5-HT e 5-HIAA são semelhantes em ambos os sexos. No entanto, no córtex, as fêmeas apresentam uma concentração de 5-HT muito menor do que os machos. Porém, a concentração de 5-HIAA foi semelhante. Como o tratamento com FLX reduziu os níveis intracelular de 5-HT no hipocampo, tanto de machos quanto de fêmeas, podemos sugerir que a FLX inibiu o transportador de 5-HT (SERT). Já que a incubação in vitro com 5-HT dos tecidos dos animais tratados com FLX aumentou as concentrações de 5-HT igualmente para machos e fêmeas, concluímos que o sistema cortical serotoninérgico das fêmeas funciona do mesmo modo que o dos machos, porém, com quantidades reduzidas de 5-HT.Abstract : Sex differences are reported in the response to antidepressants in the forced swimming test. The repeated forced swimming test is planned to evaluate the acute and chronic effect of antidepressant treatment in the same group of rats. Repeated FST consists of 15 min of swimming (pretest) followed by 5 min of swimming in the first (test), seventh (retest 1) and fourteenth (retest 2) day after pretest. In male rats, the repetition induces an increase in the immobility time. This effect is counteracted by antidepressant treatment. The aim of this study was to compare the effects of fluoxetine (FLX) in male and female rats exposed to the repeated FST. For that, male and female rats were trained to ingest a 10% sucrose solution for 7days. After that, different groups were assigned. Males received either sucrose 10% (Veh) or FLX 2,5mg/Kg. Females received Veh, FLX 1mg/Kg, FLX 2,5mg/Kg or FLX 5mg/Kg. Surprisingly, the repetition of the test failed to significantly increase de immobility time in males, however, this effect can be due to the sucrose, since it is palatable to rodents. The immobility time in females was also not affected. The chronic treatment with FLX reduced the immobility time in males, but not in females. Considering this data, we hypothesized that could exist a sexual dimorphism in the serotonergic system of this animals. To investigate that, the animals were decapitated under anaesthesia and brain regions were dissected. These regions were either incubated in vitro with vehicle or serotonin (5-HT) and further analyzed by HPLC with electrochemical detection. We found that, in the hippocampus, 5-HT and 5-HIAA concentrations were similar in both sexes. However, in the cortex, females had a much lower 5-HT levels than the males. However, 5-HIAA concentration was similar. Since the treatment with FLX reduced 5-HT levels in the hippocampus of both male and female, we can assume that FLX was inhibiting the 5-HT transporter (SERT). Since in vitro incubation with 5-HT in the tissues of the animals treated with FLX increased the 5-HT concentrations equally in both male and female brain tissues, we can assume that the females cortical system works the same as males, but with a decreased concentration of 5-HT

Bibliometric trend analysis of non-conventional (alternative) therapies in veterinary research

Background: There is an increased interest in Non-Conventional Therapies (NCTs), often referred to as complementary and alternative medicines, in veterinary clinical practice. Aim: To map the bibliometric outputs of NCTs in veterinary medicine, and identify which are most prevalent, and the extent to which their publishing has increased. Methods: Text mining algorithms were applied to detect 17 NCTs-related terms (acupuncture, ayurveda/ayurvedic, traditional Chinese medicine, traditional medicine, chiropractic, electroacupuncture, essential oil, plant extract, ethnopharmacology, herbal medicine, homeopathy, low-level laser therapy, medicinal plant, natural product, osteopathy, phytotherapy, and massage) in the title, abstract or keywords of all retrievable literature until 2020 under the PubMed MeSH term ‘veterinary’ (N = 377 556). Point prevalence, incidence by decade and cumulative incidence were calculated. Results: Bibliometric trend analysis revealed an overall increase in NCTs-related terms over the last 20 years, with a substantial growth of studies mentioning plant extracts, essential oils and medicinal plants. Traditional Chinese medicine, herbal medicine and natural product have also increased in the same period, although their numbers remain low. Conversely, reference to acupuncture has decreased in the last decade when compared with the previous decade, whereas references to homeopathy, electroacupuncture, osteopathy and chiropractic remained scarce, suggesting that their use in veterinary clinical practice may not be based on published evidence. Conclusion: Further reviews to explore this issue are warranted, differentiating secondary from primary literature, and assessing relevance and methodological quality of individual studies, following the principles of evidence-based veterinary medicine

Development of the Coordination Dimension of Relational Capabilities: Comparison between For- Profit and Non-profit Technology Transfer Partnerships

In order to ensure the success of a technology transfer partnership for-profit or non-profit, it is necessary to understand which relational capabilities (RC) to explore. This article analyses which factors can assist in the development of the coordination dimension of RC, in cooperation with the development of non-profit and profit-oriented technologies, highlighting their similarities and differences. The method used was multi-case qualitative research, studying two groups (group N and group P), each with 5 entities. The main differences highlighted is the increase of social credibility for the group N and the knowledge dissemination of the partners and the processes improvement for the group P. Within this research, it was possible to deepen the model of Alves (2015), regarding the inclusion of factors that can help the development of RC Management dimensions. Understanding capabilities development in each alliance is the implication of the study

Prolonged caffeine intake decreases alveolar bone damage induced by bingelike ethanol consumption in adolescent female rats

Ethanol consumption has been reported to negatively impact on periodontal disease. In particular, oral cavity disorders occur upon ethanol exposure during adolescence, a life period associated with particular patterns of short and intense (‘binge-like’) ethanol consumption that is most deleterious to oral health. The hazardous central effects of ethanol have been linked to the overfunction of adenosine receptors, which are antagonized by caffeine, a bioactive substance present in numerous natural nutrients, which can also modify bone metabolism. The aim of this study was to investigate the effects of caffeine on alveolar bone damage induced by an ethanol binge drinking paradigm during adolescence. Female Wistar rats (35 days old; n = 30) were allocated to six groups: control (vehicle), ethanol (3 g/kg/day; 3 days On-4 days Off challenge), caffeine (10 mg/kg/day), caffeine plus ethanol, SCH58261 (0.1 mg/kg/day, an antagonist of A2A receptors), and SCH58261 plus ethanol. Bone micromorphology and vertical bone loss were analyzed by computed microtomography. Our data showed that ethanol binge drinking reduced alveolar bone quality, with repercussion on alveolar bone size. This ethanolinduced alveolar bone deterioration was abrogated upon treatment with caffeine, but not with SCH58261. This shows that caffeine prevented the periodontal disorder caused by ethanol binge drinking during adolescence, an effect that was not mediated by adenosine A2A receptor blockad

O córtex infralímbico e as respostas sexualmente dimórficas de ratos no teste do nado forçado: implicações para o mecanismo de ação dos antidepressivos

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2019.A maior parte dos antidepressivos atuais é da classe dos inibidores seletivos de recaptação de serotonina (5 HT) ( Os ISRS inibem o transportador de 5HT ( poucos minutos após o tratamento contudo o aumento da disponibilidade extracelul ar da 5 HT e os efeitos clínicos aparecem após tratamento contínuo. Uma explicação coerente para este intervalo é a dessensibilização dos receptores inibitórios do tipo 1A (5 HT 1A pré sinápticos cuja ativação impediria a liberação da 5 HT nas aferências d os neurônios seroton érgicos. Após a dessensibilização dos 5 HT 1A pré sinápticos, a 5 HT se acumularia em áreas de projeção, como o córtex infralímbico ( inibindo sua atividade pela interação com 5 HT 1A pós sinápticos que então, promoveria os efeitos an tidepressivos ou comportamentais. A maioria dos dados formando este arcabouço teórico foi obtida em indivíduos do sexo masculino, entretanto existem evidências em humanos e animais que os efeitos dos ISRS são sexualmente dimórficos. Em nosso laboratório ob servou se que ratos Wistar tiveram respostas sexualmente dimórficas ao tratamento crônico com fluoxetina ( um ISRS, no teste de nado forçado ( o tempo de imobilidade dos ratos machos diminuiu enquanto das fêmeas permaneceu inalterado ou aumentou. No presente trabalho estudou se a hipótese de que a neurotransmissão seroton érgica no IL de ratos Wistar fosse sexualmente dimórfica, explicando assim as repostas distintas entre machos e fêmeas ao tratamento com o ISRS. Primeiro investigou se ex vivo a capacidade do SERT do encéfalo de ratos machos e fêmeas de captar 5 HT e ser inibido pela FLX. Em seguida investigou se sua participação na regulação da imobilidade no TNF de ratos de ambos os sexos. Para investigar se as ações dos ligantes do s receptores 5 HT 1A infundidos no IL eram inibi tórias ou excita tórias comparou se seus efeitos aos do agonista GABA A m uscimol. A capacidade do SER T de captar 5 HT e de ser inibido por FLX foram similares nos encéfalos de machos e fêmeas A infusão do agonista 5 HT 1A 8 OH DPAT, no IL reduziu mais o tempo de imobilidade dos ratos machos no TNF do que das fêmeas. O antagoni sta 5 HT 1A, W AY10063 5 infundido no IL preveniu os efeitos do 8 OH DPAT intra IL nos machos enquanto reduziu per se o tempo de imobilidade das fêmeas no TNF. O muscimol intra IL reduziu igualmente o tempo de imobilidade no TNF dos ratos machos e fêmeas. Ass im, concluiu se que 1 as respostas sexualmente dimórficas dos ratos no TNF foram independentes da função do SERT; 2 a inibição do IL foi necessária e suficiente para diminuir a imobilidade no TNF nos ratos machos e fêmeas; 3 a inibição do IL via ativaçã o de 5 HT 1A parece maior nos machos que nas fêmeas; 4 a influência tônica da 5 HT sobre o IL parece maior em fêmeas que em machos. Os dados sugerem que a sensibilidade dos receptores 5 HT 1A do IL dos machos é maior que das fêmeas. Diferentes característi cas dos 5 HT 1A no IL de machos e fêmeas poderiam explicar respostas dimórficas aos ISRS no TNF.Abstract: Most of antidepressants used nowadays are from the family of selective serotonin (5-HT) reuptake inhibitors (SSRI). The SSRIs inhibit the transport protein (SERT) a few minutes after treatment. However, the increase of the extracellular availability of 5-HT and the clinical effects only appear after chronic treatment. An explanation for this effect is the desensitization of the pre-synaptic inhibitory receptor type 1A (5-HT1A), whose activation would stop the liberation of 5-HT from the 5-HT neurons afferences. After the desensitization of the pre-synaptic 5-HT1A, 5-HT levels would increase in the projection areas, like the infralimbic cortex (IL), inhibiting its activity by the interaction with post-synaptic 5-HT1A which, then, would promote the behavioral antidepressant effects. Most data that form this theoretical background was performed in male subjects. However, there are evidence that the effects of SSRI treatment are sexually dimorphic. In our lab we observed that Wistar rats had different behavioral responses to the chronic treatment with fluoxetine (FLX), a SSRI, according to sex in the forced swimming test: The immobility time of males was decreased after treatment, while in females, it remained unaltered or slightly increased. In the present work, we studied the hypothesis that the serotonergic neurotransmission in IL of Wistar rats was sexually dimorphic, so explaining the different responses between males and females after SSRI treatment. First, we investigated ex vivo the capacity of SERT to uptake 5-HT and be inhibited by FLX in male and female brains. Then, we quantified the expression of 5-HT1A receptors and its part in the regulation of immobility in the forced swimming test (FST). To investigate if the inhibition of the IL was necessary to the behavior, males and females received muscimol, a GABAA agonist, infusion in this region. Regarding SERT, its capacity to uptake 5-HT and be inhibited by FLX was similar in males and females. The expression of 5-HT1A varied slightly, but its influence on the immobility in the FST was sexually dimorphic. The infusion of 8-OH-DPAT, a 5-HT1A agonist, in the IL reduced immobility time in males, but not as much in females. The antagonist of 5-HT1A, WAY100635 prevented the effects of 8-OH-DPA in males, while slightly reducing immobility in females per se. Infusion of muscimol equally reduced immobility time in both males and females. Then, we can conclude that: 1- the sexually dimorphic responses in the FST were independent of SERT function; 2- The inhibition of IL was necessary and sufficient to decrease immobility in the FST in both males and females; 3- The inhibition of IL via activation of 5-HT1A seem bigger in males than in females; 4- The tonic influence of 5-HT on IL seems bigger in females than in males. Our data suggest that the sensibility os 5-HT1A in the IL of males is bigger than in females. Different characteristics os 5-HT1A in the IL of males and females may explain the sexually dimorphic effects of SSRIS in the FST

A Systematic Review and Meta-Analysis on the Neurogenic theory Underlying the effects of antidepressants drugs on behavior

The consumption of antidepressant drugs used in psychiatric treatments doubled according to the Organization for Economic Cooperation and Development (OECD) between 2000 and 2015. Current treatments using antidepressant drugs are very effective; even with the mechanism of action of these drugs not being fully understood. Recently, advances in the area are based on theories of reversal of hippocampal cell loss with the treatment of depression. The basis of study is anchored in the causes of psychic disorders and neurochemical deficiencies. For many years, we believed that the CNS became a rigid, unmodifiable structure, and in case of injury, its cells were neither reconstituted nor reorganized. However, in recent years, we have discussed the ability to modify and adapt the Central Nervous System (CNS) in an attempt to regenerate from scientific advances. In this sense, we call it "neuroplasticity" with the capacity of existing neural circuitries, addition of new neurons or remodeling of synapses. With the evolution of neuroscience, hypotheses have emerged that neuroplasticity is involved with the efficacy of antidepressant drugs (in this study, the class of Selective Serotonin Reuptake Inhibitors - SSRI). For the author, there is challenging evidence regarding the hypothesis related to monoamines, proposing that such efficacy may originate in the high concentration of serotonin, noradrenaline, dopamine or in monoaminergic neurotransmissions. There is evidence that the morphological loss of neurons is related to long-term hippocampal depression or that the neuroplasticity, monoaminergic, neurotransmitter and neurogenesis processes of this region may interfere with the effect of drugs in the depressive state. The structural plasticity of the hippocampus depends on the process of neurogenesis - origin of new neurons - acting on the mechanism of action of antidepressants. Due to this relationship, we understand that neurogenesis in the hippocampal region has effects underlying antidepressants. Therefore, the objective of this study is to systematically review the evidence supporting the contribution of different neurobiological mechanisms to the effects of antidepressants on behavior

Terapia laser de baixa potência (λ= 904nm) na reparação de defeito osteocondral experimental da cabeça umeral de cães

Foi avaliado o processo de reparação de defeito osteocondral experimental na cabeça do úmero de cães, após a aplicação de laser a diodo de arsenieto de gálio (As-Ga). As aplicações de laser As-Ga foram realizadas com um aparelho de 45 W (watts) de intensidade máxima e comprimento de onda de 904 nm, na dose de quatro J/cm2 , em cada um dos três pontos irradiados na área da lesão. Trinta e dois animais foram separados aleatoriamente em dois grupos, tratado (GT, n = 16) e controle (GC; n = 16). A reparação das lesões aconteceu a partir da diferenciação de células mesenquimais provenientes da medula óssea que migraram por túneis vasculares e foi observada nos diferentes tempos pós-operatórios: 7, 21, 35 e 60 dias (subgrupos 1, 2, 3, e 4, respectivamente). Nos animais tratados com laser observou-se rápida transformação do tecido pouco diferenciado em tecido ósseo, que estava relacionada à abundante vascularização. O avanço da linha de maré, observado nos animais do GC, representou alteração da mecânica da articulação e da natureza e distribuição das forças aplicadas na cartilagem articular lesada. A análise histológica da membrana sinovial demonstrou variados graus de sinovite em ambos os grupos. Foi evidenciada a potencialização da reparação da cartilagem articular e da osteogênese local no grupo submetido a laserterapia.This study evaluated the repairing process on the articular surface of dog humeral head after experimental osteochondral defect with low-potency laser therapy (l = 904nm) with gallium arsenate diode laser. Thirty-two dogs were randomly allocated into one of two experimental groups, treated (TG, n = 16) and control (CG, n = 16). The injury repairing occurred via differentiation of mesenchymal cells originating in the bone marrow which migrated through vascular tunnels and was observed at different post surgery periods: 7 th , 21 st , 35 th e 60 th days (subgroups 1, 2, 3, e 4, respectively). In treated animals it was observed a rapid transformation of less differentiated tissue into bone which was related to an abundant vascularization. The tidemark advance observed in animals from CG represented mechanical alteration in the articulation and alteration in nature and distribution of the applied forces in the injured articular cartilage. The histological analysis of the synovial membrane demonstrated various degrees of synovitis in both control and treated groups. The laser therapy increased repairing articular cartilage potential and local osteogenesis

Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages so cell ab innate lymphoid cells lineages

Innate lymphoid cells (ILCs) are a recently recognized group of lymphocytes that have important functions in protecting epithelial barriers against infections and in maintaining organ homeostasis. ILCs have been categorized into three distinct groups, transcriptional circuitry and effector functions of which strikingly resemble the various T helper cell subsets. Here, we identify a common, Id2-expressing progenitor to all interleukin 7 receptor-expressing, “helper-like” ILC lineages, the CHILP. Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages, but not into conventional natural killer (cNK) cells that have been considered an ILC1 subset. Instead, the CHILP gave rise to a peculiar NKp46+ IL-7Rα+ ILC lineage that required T-bet for specification and was distinct of cNK cells or other ILC lineages. Such ILC1s coproduced high levels of IFN-γ and TNF and protected against infections with the intracellular parasite Toxoplasma gondii. Our data significantly advance our understanding of ILC differentiation and presents evidence for a new ILC lineage that protects barrier surfaces against intracellular infections