Submitted by Isaac Francisco de Souza Dias (isaac.souzadias@ufpe.br) on 2016-01-22T17:40:13Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTACAO - RAQUEL ATUALIZADAcomDATAdeAprovação.pdf: 1745460 bytes, checksum: 52bc639e830160484707e3dc244d4b0e (MD5) / Made available in DSpace on 2016-01-22T17:40:13Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTACAO - RAQUEL ATUALIZADAcomDATAdeAprovação.pdf: 1745460 bytes, checksum: 52bc639e830160484707e3dc244d4b0e (MD5) Previous issue date: 2015-03-02 / A serotonina (5HT) atua como um neuromodulador amplamente distribuído no sistema nervoso central e desempenha função essencial na regulação do desenvolvimento do encéfalo. Alterações na sinalização de 5-HT através da exposição a inibidores da recaptação de serotonina durante a fase perinatal têm o potencial de afetar o desenvolvimento neural e podem resultar em alterações comportamentais na vida adulta. Mais investigações são necessárias de forma a incluir ambos os sexos no estudo desses efeitos. Dessa forma, o objetivo deste estudo foi investigar as repercussões do tratamento neonatal com fluoxetina, sobre a ontogênese de reflexos, desenvolvimento somático e o consumo alimentar em ratos machos e fêmeas. Foram utilizados quatro grupos experimentais segundo o gênero (macho ou fêmea) e tratamento (fluoxetina ou salina): Machos Salina (MS, n=16); Machos Fluoxetina (MF, n=18); Fêmeas Salina (FS, n=19) e Fêmeas Fluoxetina (FF, n=18). Os animais do grupo fluoxetina receberam fluoxetina na dose de 1μl/g do 1º ao 21º dia pós-natal e os animais que fizeram parte do grupo salina solução salina a 0,9%, 1μl/g. Foram registrados no período neonatal (1 a 21 dias): a ontogênese reflexa, o desenvolvimento somático, as características físicas e a consumo alimentar durante a lactação, bem como no período pós natal (22 - 31 dias): o peso corporal e consumo alimentar pós-desmame. Apesar da administração crônica de fluoxetina no período neonatal não ocasionar alterações no consumo alimentar, causa retardo na ontogênese reflexa, menor ganho de peso e desenvolvimento somático mais marcante no sexo masculino. Esses achados sugerem uma resposta sexo-específica relativa à manipulação do sistema serotoninérgico. Essas alterações confirmam que a serotonina desempenha um papel importante na plasticidade durante o período de desenvolvimento do sistema nervoso, de forma diferente entre machos e fêmeas. / Serotonin (5HT) acts as a neuromodulator widely distributed in the central nervous system and plays a critical role in the regulation of brain development. Changes in 5-HT signaling by serotonin reuptake inhibitors exposure during the perinatal period can affect neural development and may result in behavioral changes in adulthood. Further investigations are necessary including both sexes to study these effects. Thus, the aim of this study was to investigate the impact of neonatal treatment with fluoxetine on the ontogeny of reflexes, somatic development and food intake in male and female rats. The animals were formed by four groups according to gender (male or female) and treatment (fluoxetine or saline). Animals in the fluoxetine group received fluoxetine at 1μl/g on 1º to 21 postnatal day and the animals that were part of the saline group received saline 0.9%, 10 ml / kg. In the neonatal period (1-21 days) were recorded: reflex ontogeny, somatic development, physical characteristics and food intake during lactation. In the postnatal period (22-31 days) were recorded: body weight and post-weaning food intake. Despite the chronic administration of fluoxetine in the neonatal period did not cause changes in food intake, it causes delay in the reflex ontogeny, lower weight gain and somatic development and most striking in males. In summary, these findings suggest a sex-specific response on the manipulation of the serotonergic system. These changes confirm that serotonin plays an important role in regulating the plasticity of the nervous system during development period, differently from males and females.

Made available in DSpace on 2014-06-12T23:01:18Z (GMT). No. of bitstreams: 2 arquivo4241_1.pdf: 679441 bytes, checksum: 0342bff85ec533fb1fe2e965af7ce73b (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2009 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Influências genéticas e ambientais atuam sobre o Sistema Nervoso Central (SNC) durante o processo de desenvolvimento. Uma nutrição adequada é essencial para a formação do SNC, organização funcional e para desenvolvimento do organismo. Estudos utilizando dietas semi-sintéticas foram desenvolvidos para reproduzir em animais de laboratório características clínicas, bioquímicas e patológicas, observadas em humanos desnutridos. A dieta básica regional (DBR) foi proposta para estudar a desnutrição característica dos habitantes de baixa renda da zona da mata de Pernambuco. O presente estudo avaliou o perfil morfológico (densidade e número de células neuronais) do córtex visual de ratos Wistar submetidos a dois tratamentos nutricionais: dieta padrão de biotério (Labina®, 23% de proteína) e dieta hipoprotéica (DBR, 8% de proteína), originando 6 grupos experimentais: N5, N7 e N9 - animais nutridos com Labina® durante 5º., 7º. e 9º. meses respectivamente, e D5, D7 e D9 - animais desnutridos por DBR durante os mesmos períodos. Após o tratamento nutricional, os animais foram sacrificados e os cérebros retirados, processados histologicamente e avaliados através de estudos morfométricos. Observou-se que a desnutrição induzida por DBR provocou uma redução significativa na massa corporal dos animais de todos os grupos. A redução foi decrescente ao longo da idade, pois aos 5 meses os animais DBR pesavam, em média, apenas 27,7% do peso total do animal normonutrido, aos 7 meses, 29,1% e por fim aos 9 meses os animais DBR pesavam cerca de 32% do peso dos normonutridos. A comparação feita entre os grupos mostrou que o peso cerebral também foi visivelmente reduzido nos animais desnutridos. A maior redução no peso cerebral ocorreu no grupo D9 onde a média do peso dos cérebros desse grupo correspondia a 81,55% do peso cerebral do grupo N9. Não houve diferença significativa em relação ao número de neurônios por campo e nem em relação à média da área do soma dos neurônios. Tais achados indicaram que a desnutrição induzida pela DBR no pós-desmame embora não cause alterações na citomorfologia do córtex cerebral tem repercussões sobre a evolução ponderal e encefálica

Global cerebral ischemia is an established animal model mimicking the effects of cardiac arrest in humans. It is characterized by selective neuronal damage in the hippocampus and significant behavioural and cognitive impairments. In this light, novel therapeutic compounds with numerous physiological targets as well as neuroprotective capabilities and the capacity to lessen residual cognitive deficits pose as great candidates in the treatment of ischemic pathology. The current thesis investigates the possible therapeutic properties of resveratrol (3, 4, 5´trihydroxystilbene), a naturally occurring phytoalexin present in the skin of grapes, against cerebral ischemia-induced neuronal degeneration and cognitive impairments, as well as elaborate on possible mechanisms of action of the compound in male Wistar rats. In Article 1, neuronal density assessment and behavioural testing following chronic pretreatment with resveratrol at two doses (1 and 10 mg/kg) revealed that the compound has important neuroprotective properties at short and long post-ischemic intervals. Despite comparable neuronal protection, the two resveratrol doses showed distinct behavioural effects, highlighting independent actions of the polyphenol on discrete physiological systems mediating cellular survival and behavioural recovery. Articles 2 and 3 investigated possible mechanisms of action of the polyphenol that have not yet been explored with regards to cerebral ischemia. Specifically, Article 2 demonstrated that resveratrol influences markers of plasticity in both ischemic and control animals as well as promotes angiogenesis in the hippocampal region postischemia. Further elaborating on documented effects attributing non-neuronal mechanisms of action of resveratrol in reducing glial activation postischemia, Article 3 highlighted important regulatory effects of resveratrol on mediating glial type-1 glutamate transporter expression at a short reperfusion interval. These findings support the notion of multiple biological targets by resveratrol and highlight its potential role in attenuating forebrain ischemia-induced neuronal degeneration through multiple physiological targets, while cautioning against possible dose-related effects on behaviour and in healthy controls.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Its cause(s) are predominantly unknown; however, a subset of cases has a genetic origin. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of PD. Cases are clinically indistinguishable from idiopathic PD and display incomplete penetrance. Thereby, it is predicted that genetic vulnerability combined with environmental factors cause pathogenesis. However, the identity of these factors is unknown. Unfortunately, LRRK2`s native and pathogenic biological function(s) remain to be defined; owing to obstacles including a complex protein structure and the lack of pathological phenotypes in LRRK2 research models. To address the knowledge gap in LRRK2 biology, we set out to investigate the role of LRRK2 in the central nervous system (CNS). We generated and characterized a disease-mimicking D. melanogaster model of LRRK2-linked PD. This system was utilized to perform an in vivo, unbiased, high-throughput genetic screen to identify candidate interactors of LRRK2. Successful identification of a discrete number of genetic interactors was accomplished and, coupled with published evidence, highlighted the pursuit of subsequent mitochondrial-related investigations of LRRK2. These studies were performed using the M. musculus model system. Since LRRK2 murine models lack disease-relevant phenotypes, and LRRK2’s incomplete penetrance is predicted to be the result of gene-environment interaction, we employed the mitochondrial-targeting exogenous neurotoxin – MPTP/MPP+, to investigate neuronal mitochondrial phenotypes and subsequent survival in the context of LRRK2. Using the pathogenic R1441 GTPase-linked mutation, we did not observe altered neuronal mitochondrial length phenotypes or enhanced CNS sensitization to MPTP/MPP+-induced death; highlighting that MPTP-mediated, mitochondrial-centered mechanisms of action should be approached cautiously in the context of R1441-LRRK2. Collectively, the work presented herein has unveiled novel targets for the exploration of LRRK2 biological function and encourages the investigation of alternative pathogenic trigger mechanisms in the context of LRRK2-linked PD.

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The effects of cannabinoid agonists on spontaneous neuronal network activity were characterized in murine spinal cord and auditory cortical cultures with multichannel extracellular recording using photoetched electrode arrays. Different cultures responded reproducibly with global decreases of spiking and bursting to anandamide and methanandamide, but each agonist showed unique minor effects on network activity. The two tissues responded in a tissue-specific manner. Spontaneous activity in spinal tissue was terminated by 1 μM anandamide and 6.1 μM methanandamide. Cortical activity ceased at 3.5 μM and 2.8 μM respectively. Irreversible cessation of activity was observed beyond 8 μM for both tissues and test substances. Palmitoylethanolamide, demonstrated that CB2 receptors were not present or not responsive. However, the data strongly suggested the presence of CB1 receptors.

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