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The molecular mechanism of Chinese medicine Uncaria Rhynchophylla (gouteng) for inducing autophagy and protecting neurons in Parkinson's diseaseChen, Leilei 27 August 2015 (has links)
Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (α- syn) is the major component of Lewy bodies (LBs) in PD, and impairment of the autophagy-lysosomal pathway has been linked to its accumulation. In our previous study, we identified corynoxine B (Cory B), an oxindole alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks (Gouteng in Chinese), as a Beclin-1-dependent autophagy enhancer. In this work, we continued to screen autophagy enhancers from Gouteng alkaloids, and found corynoxine (Cory), an isomer of Cory B, also induces autophagy in different neuronal cell lines and primary neurons. Meanwhile, Cory promotes the formation of autophagosomes in the fat bodies of Drosophila. By inducing autophagy, Cory promotes the clearance of wild-type and A53T α-syn in inducible PC12 cells. Interestingly, different from its enantiomer Cory B, Cory induces autophagy through the Akt/mTOR pathway as evidenced by the reduced levels of phospho-TSC2, phospho-Akt, phospho-mTOR and phospho-p70 S6 Kinase. To identify the different pathway between Cory and Cory B, we performed phosphoproteomic study on N2a cells. With the help of iGPS (In vivo Group-based Prediction System), protein kinases which were significantly regulated by Cory or Cory B were predicted. Based on these kinases, we drew the detailed kinasesubstrates network regulated by Cory or Cory B. The structures of Cory and Cory B differ only in the stereochemistry at the spiro carbon; however, Cory has more effect on the CAMK, Trb and TSSK families, while CDK and CDKL families are more sensitive to Cory B. Furthermore, we established a rotenone rat model of PD via injecting rotenone into the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), and evaluated the neuroprotection of Cory and Cory B on this rat model. Motor dysfunction, decreased TH level, impairment of autophagy, aggregation of α-syn and activation of microglia were all found on this PD model, which were consistent with previous reports. After the treatment of Cory or Cory B, we found that both Cory and Cory B improve motor dysfunction, increase the TH level, and inhibit microglial activation. Both Cory and Cory B decrease the puncta number of aggregated α-syn, likely due to the induction of autophagy. All these results indicate the neuroprotection of Cory and Cory B against PD. Collectively, our findings (1) provide the original finding of Coy to be an autophagy enhancer with experimental evidences that Cory inhibited the pathway of Akt/mTOR; (2) provide cellular and animal experimental evidences for developing Cory or Cory B as anti-PD agent, by inducing autophagy in neurons; and (3) provide candidate pathways to identify the primary molecular target of Cory or Cory B, which may turn out to be potential therapeutic targets for treating PD. Keywords: Parkinson’s disease, Cory, Cory B, autophagy, phosphoproteomic, neuroprotection.
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Efeito neuroprotetor da hipotermia epidural após a lesão medular contusa em ratos / Neuroprotective effect of epidural hypothermia after spinal cord lesion in ratsMarcello Oliveira Barbosa 08 April 2014 (has links)
Introdução: A lesão da medula espinhal é uma entidade clínica grave e extremamente incapacitante. Muitos esforços estão sendo realizados para melhorar a resposta neurológica ao trauma da medula espinhal. Dentre eles, destacamos o uso de agentes farmacológicos, a descompressão e estabilização cirúrgica precoces e a hipotermia. A hipotermia pode ser induzida de forma sistêmica ou local. Várias complicações, como arritmias cardíacas, coagulopatias e infecções, foram associadas ao uso sistêmico da hipotermia. Porém, sua aplicação local demanda a necessidade de intervenção cirúrgica de emergência e manejo pós-operatório complicado. Objetivo: Avaliar o efeito neuroprotetor da hipotermia epidural em ratos. Material e método: Foram arrolados 30 ratos Wistar pesando entre 320-360 g e divididos aleatoriamente em dois grupos: o grupo da hipotermia epidural e o grupo controle, com 15 ratos cada. Uma contusão medular produzida por queda padronizada de peso de 10 g, a 25 mm de altura, usando o New York University (NYU) Impactor, foi realizada após a laminectomia em T9-10 em todos os ratos. Os ratos do grupo da hipotermia foram submetidos ao resfriamento a 9-10 °C por um período de 20 minutos, logo após a contusão medular. Os grupos foram analisados durante seis semanas quanto à função motora utilizando-se a escala BBB e o teste do plano inclinado. Ao final da sexta semana, foi realizado ainda o exame de potencial evocado motor dos ratos, cujos resultados foram comparados entre os dois grupos. Resultados: A avaliação da função motora através da aplicação da pontuação da escala BBB ao longo das seis semanas não evidenciou diferenças estatisticamente significantes entre os dois grupos. Não encontramos diferenças estatísticas na avaliação motora através da pontuação do teste do plano inclinado ao longo das seis semanas do estudo. Os valores de latência e amplitude do potencial evocado motor não mostraram diferenças estatísticas significantes entre os grupos ao final da última semana do estudo. Conclusão: A hipotermia não apresentou efeito neuroprotetor quando aplicada no sítio da lesão, logo após a contusão medular, no espaço epidural de ratos Wistar / Introduction: Spinal cord injury (SCI) is a critical and extremely disabling clinical condition. Considerable effort has been made to improve the neurological response to the spinal cord lesion. We must highlight pharmacological agents, early surgical decompression and stabilization and hypothermia. Therapeutic hypothermia can be achieved systemically or locally. Many complications have been associated to the systemic hypothermia, such as cardiac arrhythmias, coagulopathies and infection. However, local application demands surgical intervention and difficult post operative care. Objetive: To evaluate the neuroprotective effect of epidural hypothermia in rats. Methods: Wistar rats (n = 30; weighting 320-360 g) were randomized in two groups: the hypothermia and the control group, with 15 rats in each. A spinal cord lesion was produced by the standardized drop of a 10 g-weight from a height of 2,5 cm, using the New York University Impactor, after the laminectomy at the T9-10 level. Rats of the hypothermia group underwent epidural hypothermia for 20 minutes immediately after spinal cord injury. Motor function was assessed during six weeks using the BBB motor scores and inclined plane test. At the end of the last week, neurologic status was monitored by the motor evoked potential exam and the results were compared between the two groups. Results: Analysis of the BBB scores during the six-weeks period did not show any statistically significant difference between the two groups. We did not find any significant difference between the groups in the scores of the inclined plane test during the six-weeks period. Latency and amplitude values of the motor evoked potential exam did not show any statistically significant difference between the two groups at the end of the study. Conclusion: Hypothermia did not produce any neuroprotective effect when applied immediately after spinal cord contusion, at the injury level and in epidural space of Wistar rats
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Atividade fisica e neuroproteção em camundongos adultos após indução de status epilepticus por pilocarpina / Physical activity and neuroprotection in adult mice after pilocarpine induced status epilepticusSartori, César Renato, 1973- 21 June 2005 (has links)
Orientador: Francesco Langone / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-04T18:58:52Z (GMT). No. of bitstreams: 1
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Previous issue date: 2005 / Resumo: O modelo de epilepsia induzida por pilocarpina em camundongos reproduz a Epilepsia do Lobo Temporal (ELT) em humanos. Animais submetidos à indução de status epilepticus apresentam alterações comportamentais, eletroencefalográficas e lesão neuronal compatíveis com esta condição. Estudos recentes relatam relevantes efeitos positivos da prática de atividade física sobre o sistema nervoso tanto em humanos como em modelos animais. Dentre estes efeitos figuram o aumento da sobrevivência neuronal e da resistência cerebral a diferentes insultos, promoção da angiogênese, estímulo da neurogênese, fortalecimento da potenciação de longa duração no hipocampo, melhora da aprendizagem e memória e contribuição para a manutenção da função cognitiva durante o envelhecimento. Todos estes efeitos conferem à atividade física um grande potencial neuroprotetor. Além disso, foram relatados benefícios decorrentes desta intervenção ambiental diretamente em pacientes com epilepsia e em animais submetidos à epilepsia induzida. Contudo, não há dados na literatura sobre o possível efeito neuroprotetor da atividade física no modelo de epilepsia induzida por pilocarpina em camundongos. Assim sendo, o presente estudo teve por objetivo investigar os efeitos da atividade física voluntária crônica sobre a perda neuronal no hipocampo e suas conseqüências na função mnemônica de camundongos submetidos a este modelo experimental. Trinta e dois camundongos Swiss foram divididos em quatro grupos experimentais (n=8): Saudável Sedentário (SS), Saudável Corredor (SC), Epiléptico Sedentário (ES) e Epiléptico Corredor (EC). Quarenta e oito horas após a indução do status epilepticus, ou sua simulação, foi proporcionado aos animais dos grupos corredores (SC e EC) o acesso a uma roda de atividade instalada em suas respectivas gaiolas por um período de 28 dias. Após este período os animais foram testados no labirinto aquático de Morris para avaliação da memória de referência espacial. Ao final dos testes os animais foram perfundidos com paraformaldeído (4% em tampão fosfato) e os cérebros removidos e processados para inclusão em parafina. Foram então obtidos cortes frontais do cérebro (8µm) para avaliação da extensão da lesão tecidual (coloração de Nissl), da presença de neurônios em degeneração (Fluoro Jade B) e da proliferação celular (PCNA) na formação hipocampal dorsal. Os animais dos grupos SS e SC não apresentaram lesão neuronal ou neurodegeneração, como esperado; também não diferiram entre si na proliferação celular e no teste de memória de um modo geral. Os animais dos grupos ES e EC apresentaram lesão neuronal e neurodegeneração, não sendo constatadas diferenças entre sedentários e corredores. Por outro lado, os animais ES revelaram maior proliferação celular comparados aos EC. Os animais do grupo EC apresentaram desempenho significativamente melhor nos testes de memória quando comparados aos animais ES. Assim, nossos dados revelaram que, a despeito de não ter ocorrido proteção contra lesão histológica, a atividade física melhorou significantemente o desempenho dos animais submetidos ao status epilepticus no teste do labirinto aquático de Morris, indicando que mesmo após lesão neurológica a atividade física promove melhora funcional. Acreditamos que tal melhora pode ser atribuída a mecanismos moleculares relacionados à plasticidade neuronal, que não foram identificados pelas técnicas utilizadas no presente estudo / Abstract: Pilocarpine-induced epilepsy in mice is an experimental model of the Temporal Lobe Epilepsy (TLE). Status epilepticus determined by pilocarpine adminstration leads to behavioral and electroencephalographic changes and neuronal damage similar to those observed in TLE. Recently, it has been shown that physical activity exerts neuroprotective effects, such as increase in neuronal survival, angiogenesis and neurogenesis; resistance to brain injuries, strengthening of the long term potentiation (LTP), improvement of memory and learning; and preservation of cognitive function during aging process. Particularly, physical activity also plays a positive role in epileptic patients and animals. However, there are no reports regarding the neuroprotective action of physical activity on the pilocarpine model of epilepsy in mice. In the present work, we studied the effects of the voluntary physical activity on hippocampal neuronal loss and mnemonic function of mice after the pilocarpine-induced status epilepticus. Thirty-two Swiss mice were assigned to four experimental groups (n=8): Normal Sedentary (NS), Normal Runner (NR), Epileptic Sedentary (ES) and Epileptic Runner (ER). Forty-eight hours after the status epilepticus or its simulation the animals of the runner groups (NR, ER) had access to a running wheel for 28 days. After that, the mice were submitted to the Morris Water Maze test for the evaluation of the spatial memory. Finally, the mice were perfused with paraformaldehyde (4% in phosphate buffer), the brains were dissected and processed for paraffin embedding. Frontal sections (8mm) were serially cut and used for analysis of histologic damage (Nissl staining), degenerating neurons (Fluoro Jade B) and cell proliferation (immunohistochemistry for PCNA) of the dorsal hippocampal formation. Mice of the NS and NR groups showed neither neuronal damage nor neurodegeneration. In addition, these groups were similar to each other in the Morris Water Maze test and exhibited comparable immunostainig patterns for PCNA. In contrast to the previous groups, in ES and ER groups neuronal damage and neurodegeneration were observed and equivalent. However, cell proliferation was higher in ES than in ER. Animals of the ER group had better performance in the Morris Water Maze test compared to ES mice. In conclusion, our results show that physical activity improved significantly the spatial memory of mice that had status epilepticus induced by pilocarpine, despite of having not changed the morphological evidence of neuronal damage. We believe that such improvement might be attributed to molecular mechanisms related to neuronal plasticity, which were not identified by the techniques we used in the present investigation / Mestrado / Fisiologia / Mestre em Biologia Funcional e Molecular
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Enhancement of gene silencing effects of small interfering RNAs to N-methyld-D-asparate receptors by gold nonoparticiplesIu, Yan Yu 01 January 2013 (has links)
No description available.
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Conception, synthèse et évaluation de nouveaux ligands de la protéine sigma-1 à visée neuroprotectrice / Conception, synthesis and evaluation of novel sigma-1 receptor ligands as neuroprotective agentsDonnier-Maréchal, Marion 26 September 2013 (has links)
Les maladies neurodégénaratives (MNDs) sont les troubles neurologiques les plus fréquents chez l’homme et touchent des millions de personnes à travers le monde. Elles affectent le fonctionnement du système nerveux de façon chronique et progressive et conduisent souvent au décès du malade. L’évolution de ces maladies est très variable et les traitements disponibles actuellement ne permettent pas de modifier leur progression mais seulement d’atténuer les manifestations symptomatiques.Les récepteurs σ1 correspondent à une classe unique de récepteurs transmembranaires du réticulum endoplasmique. Exprimés au niveau du SNC et en particulier dans les neurones, les lymphocytes et les oligodendrocytes, ces récepteurs sont connus pour être impliqués dans la régulation de nombreux neurotransmetteurs. Même si les mécanismes de transduction après leur activation ne sont pas complètement élucidés, de plus en plus d’études mettent en évidence le potentiel thérapeutique de ces récepteurs. En effet, depuis leur découverte, les récepteurs σ1 ont été impliqués dans de nombreuses pathologies dont des MNDs.Ces travaux de thèse s’inscrivent donc dans ce contexte. Le projet consistait à concevoir, synthétiser et évaluer de nouveaux ligands σ1 pour une utilisation en neuroprotection. Les dérivés tétrahydroquinolin-hydantoïnes préalablement conçus au laboratoire, ont montré des affinités nanomolaires envers la protéine σ1, une bonne sélectivité, une faible cytotoxicité et des propriétés ADME compatibles avec un développement thérapeutique. Evalués dans différents modèles, ces composés ont montrés des propriétés anti-inflammatoires associées à une action neuroprotective. Cependant, bien que les Tic-hydantoïnes soient des composés chimiquement stables, ils ont montré une faible stabilité métabolique. Trois nouvelles familles de composés ont donc été conçues et synthétisées afin de pallier à ces problèmes. Leurs affinités, sélectivités, cytotoxicités et propriétés ADME ont été évaluées. Des tests comportementaux ont également été réalisés sur les composés les plus intéressants afin de déterminer leur profil agoniste ou antagoniste. Finalement, le meilleur candidat, évalué dans un modèle in vivo de sclérose en plaques, a montré des propriétés neuroprotectrices intéréssantes. / Neurodegenerative diseases are the most common neurological disorders in humans, affecting millions of people worldwide. They affect the nervous systems in chronic and progressive way and often lead to the death of the patient. The evolution of these diseases is highly variable and currently available treatments do not alter their growth but only moderate symptomatic manifestations.Sigma-1 receptors represent a structurally unique class of transmembrane receptors of the endoplasmic reticulum. Expressed in the central nervous system and especially in neurons, lymphocytes and oligodendrocytes, these receptors are known to be involved in the regulation of numerous neurotransmitters. Even if the signal transduction pathway after activation of σ1 receptors is not completely understood, more and more evidences suggest that they represent a potential therapeutic target in many diseases. Indeed, since their discovery, the σ1 receptors have been implicated in various pathologies including neurodegenerative disorders. Thus, it is in this context that our interest is focused on the conception and synthesis of novel σ1 receptors ligands for the treatment of neurodegenerative diseases. Fused and optimized tetrahydroquinoline-hydantoin derivatives designed in our laboratory showed nanomolar σ1 affinity, σ2 /σ1 selectivity, very low cytotoxicity and ADME properties compatible with therapeutic development. Evaluated in different models, these compounds showed an anti-inflammatory activity associated with a neuroprotective action. However, while the Tic-Hydantoin derivatives are chemically stable, they showed a low metabolic stability. Thus, three novel families of compounds were synthesized in order to compensate for these problems. Their affinities, selectivities, cytotoxicities and their ADME properties were evaluated. Behavioural testing was carried out on the most interesting compounds to determine the agonist or antagonist profil. Finally, evaluated in in vivo model of multiple sclerosis, the best compound showed interesting neuroprotective properties.
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Stroke Study: Novel Animal Models and Innovative Treatment StrategyYu, Xinge 04 August 2016 (has links)
No description available.
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Neuroprotective effects of the active principles from selected Chinese medicinal herbs on b-amyloid-induced toxicity in PC12 cells.January 2007 (has links)
Hoi, Chu Peng. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 81-103). / Abstracts in English and Chinese. / Acknowledgements --- p.II / Abstract --- p.III / Abstract (in Chinese) --- p.V / List of Abbreviations --- p.VI / List of Figures --- p.VIII / List of Tables --- p.X / Table of Contents --- p.XI / Chapter Chapter One --- General introduction --- p.1 / Chapter 1.1 --- Alzheimer's disease --- p.1 / Chapter 1.1.1 --- Epidemiology and risk factors --- p.2 / Chapter 1.1.2 --- Clinical manifestation and course --- p.4 / Chapter 1.1.3 --- Clinical diagnosis --- p.5 / Chapter 1.1.4 --- Neuropathology and pathogenesis of AD --- p.8 / Chapter 1.1.5 --- Drug therapy of AD --- p.11 / Chapter 1.1.5.1 --- Drugs for symptomatic treatment --- p.11 / Chapter 1.1.5.2 --- Drugs based on epidemiology --- p.12 / Chapter 1.1.5.3 --- Drugs with potential disease-modifying effects --- p.14 / Chapter 1.1.5.4 --- Herbal supplements --- p.15 / Chapter 1.2 --- Models for drug discovery in Alzheimer Disease --- p.15 / Chapter 1.2.1 --- In vivo (animal) models --- p.16 / Chapter 1.2.2 --- In vitro (cellular) models --- p.18 / Chapter 1.3 --- Chinese herbs for the treatment of AD --- p.20 / Chapter 1.3.1 --- Ginkgo biloba L --- p.21 / Chapter 1.3.2 --- Magnolia officinalis --- p.24 / Chapter 1.3.3 --- Acori graminei Rhizoma (AGR) --- p.26 / Chapter 1.3.4 --- Gastrodia elata (G. elata) --- p.27 / Chapter 1.3.5 --- Rhodiola rosea L.( R. rosea) --- p.29 / Chapter 1.3.6 --- Scutellariae baicalensis --- p.30 / Chapter 1.3.7 --- Curcuma longa L.(Zingiberaceae) --- p.31 / Chapter 1.4 --- Aims of the study --- p.33 / Chapter Chapter Two --- Materials and Methods --- p.34 / Chapter 2.1 --- Materials --- p.34 / Chapter 2.1.1 --- Chemicals and reagents --- p.34 / Chapter 2.1.2 --- Materials for cell culture --- p.35 / Chapter 2.1.3 --- Instruments --- p.35 / Chapter 2.2 --- Methods --- p.36 / Chapter 2.2.1 --- Cell culture --- p.36 / Chapter 2.2.2 --- MTT cell viability assay --- p.38 / Chapter 2.2.3 --- Characterization of the cytotoxicity of Aβ peptide in NGF-differentiated PC 12 cells --- p.38 / Chapter 2.2.4 --- Screening of the neuroprotective effect of major principles from selected herbs on PC 12 cells against Aβ-induced cytotoxicity --- p.39 / Chapter 2.2.5 --- Measurement of reactive oxygen species (ROS) --- p.40 / Chapter 2.2.6 --- Measurement of intracellular calcium levels --- p.41 / Chapter 2.2.7 --- Measurement of caspase-3 activity --- p.42 / Chapter 2.2.8 --- Propidium iodide (PI) staining to evaluate apoptosis and necrosis --- p.43 / Chapter 2.3 --- Statistics --- p.45 / Chapter Chapter Three --- Results --- p.46 / Chapter 3.1 --- NGF-differentiated PC 12 cells --- p.46 / Chapter 3.1.1 --- Determination of an appropriate cell density for the screening experiments --- p.46 / Chapter 3.1.2 --- Characterization of Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells --- p.47 / Chapter 3.1.2.1 --- Cytotoxicity of Aβ-related fragments in NGF-differentiated PC 12 cells --- p.48 / Chapter 3.1.2.2 --- Dose-dependent cytotoxic effect of Aβ on PC 12 cells --- p.48 / Chapter 3.1.2.3 --- Time-dependent effect of Aβ-induced toxicity on PC12 cells --- p.50 / Chapter 3.1.3 --- Protective effect of selected active principles against Aβ1-4-induced toxicity in PC 12 cells --- p.51 / Chapter 3.2 --- Measurement of reactive oxygen species (ROS) --- p.54 / Chapter 3.2.1 --- Measurement of ROS induced by H202 --- p.54 / Chapter 3.2.2 --- Measurement of ROS induced by Aβ --- p.56 / Chapter 3.3 --- Measurement of Intracellular calcium levels --- p.57 / Chapter 3.4 --- Measurement of caspase-3 activity --- p.58 / Chapter 3.4.1 --- AMC reference standard curve --- p.59 / Chapter 3.4.2 --- Measurement of caspase-3 activity --- p.59 / Chapter 3.5 --- PI staining for evaluate apoptosis and necrosis --- p.60 / Chapter Chapter Four --- Discussion --- p.64 / Chapter 4.1 --- Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells as an in vitro model of Alzheimer's disease --- p.64 / Chapter 4.1.1 --- Cell line selection --- p.65 / Chapter 4.1.2 --- Characterization of Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells --- p.66 / Chapter 4.2 --- Screening of the neuroprotective effects of selected active principles against Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells --- p.67 / Chapter 4.3 --- Neuroprotection via inhibition of the ROS generation --- p.71 / Chapter 4.4 --- Neuroprotection via suppression of calcium homeostasis --- p.73 / Chapter 4.5 --- Neuroprotective via inhibition of Aβ-induced apoptosis --- p.75 / Chapter 4.5.1 --- Inhibition of caspase-3 activation --- p.75 / Chapter 4.5.2 --- PI staining for evaluation of apoptosis and necrosis --- p.76 / Chapter Chapter Five --- Conclusion and future work --- p.79 / Chapter 5.1 --- Conclusion --- p.79 / Chapter 5.2 --- Future work --- p.80 / References --- p.81
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Significance of a cognition-enhancing Chinese herb Fructus alpiniae oxyphyllae as a source for potential neuroprotective agents. / CUHK electronic theses & dissertations collectionJanuary 2010 (has links)
Hong, Sijia. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 197-234). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
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Investigating beta-amyloid peptide neurotoxicity from neuronal apoptosis to endoplasmic reticulum collapse: translational research back to basic science researchLai, Sau-wan., 賴秀芸. January 2009 (has links)
published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy
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Estudo do efeito neuroprotetor da estimulação magnética transcraniana e hipotermia em modelo de isquemia cerebral induzida / Study of the neuroprotective effect of the Transcranial Magnetic Stimulation and hypothermia in a animal model of induced cerebral ischemiaMacri, Fábio Teixeira 03 August 2011 (has links)
Introdução: Muitos estudos veem sendo realizados com a finalidade de identificar agentes que possam ter efeito benéfico no tratamento ou prevenção das lesões causadas nos neurônios devido à isquemia. A hipotermia já demonstrou resultados consistentes em estudos experimentais e a Estimulação Magnética Transcraniana (EMTr) já foi usada visando reduzir danos em neurônios hipocampais de animais submetidos a isquemia cerebral. Com a propriedade de aumentar ou diminuir a excitabilidade cortical a partir do estímulo magnético, estima-se que ocorra uma interferência na produção de alguns neurotransmissores e receptores de membrana, que promoveriam efeito protetor a estas células. Neste estudo avaliamos a capacidade da EMTr de proteger os neurônios de uma lesão por hipóxia, e sua possível interferência no efeito protetor da hipotermia, tentando identificar alguns mecanismos que possivelmente estariam envolvidos neste fenômeno. Métodos: Como modelo de isquemia, foram utilizados Gerbils previamente submetidos a uma avaliação de comportamento e memória por meio do teste de esquiva. O protocolo de EMTr foi a partir de sessões diárias com 25 séries de 5 segundo a 25Hz, com um intervalo de 45 segundos entre as séries, por sete dias consecutivos, com um total de 21 875 pulsos com uma intensidade de 100% do limiar motor, e sendo realizada a indução da isquemia logo após o término da última sessão, ou na isquemia após a EMTr, em sessões diárias com 25 séries de 5 segundos a 25Hz, com um intervalo de 45 segundos entre as séries, durante 3 dias consecutivos, começando imediatamente após a cirurgia. Foi mantida a temperatura de 36 °C durante o período de oclusão do vaso e os 30 minutos consecutivos, ou 31 a 32 °C quando em hipotermia. O preparo das lâminas teve cortes envolvendo a região do hipocampo, corados com hematoxilina e eosina, além de outros preparos, a marcação de TUNEL e Caspase, que visam evidenciar a ocorrência de apoptose. Resultados: Embora sem significância estatística, os animais que receberam EMTr aparentemente tiveram uma melhor performance no teste da esquiva, principalmente se aplicado após a indução da isquemia. A hipotermia demonstrou uma eficiência significativa, tanto na análise histológica quanto no teste da esquiva, associado ou não à EMTr, e nestes animais submetidos a isquemia durante a hipotermia, os que receberam EMTr tiveram área de sobrevida no hipocampo significativamente maior na análise histológica com hematoxilina e eosina. Nos animais submetidos à isquemia durante a temperatura normal, a EMTr não demonstrou aumentar a área de sobrevida das células do hipocampo. Conclusões: A EMTr (ativa ou placebo, prévia ou posterior à isquemia) pareceu ter um efeito positivo no teste de esquiva. O procedimento de estimulação pareceu bastante traumático e estressante para os animais, tendo ocorrido alguns óbitos durante a imobilização, provavelmente por asfixia. A EMTr apresentou efeito protetor significativo apenas nos animais submetidos a isquemia durante hipotermia / Introduction: Over the time many researches have been conducted with the aim of identifying agents that may have beneficial effects in the treatment or prevention of cerebral ischemia, hypothermia has shown consistent results in experimental trials and Repetitive Trans Cranial Magnetic Stimulation (rTMS) has been used in a study attempting to reduce damage in hippocampal neurons. With the property to increase or decrease cortical excitability from the repetitive magnetic stimulus, it is estimated that an interference occurs in the production of some neurotransmitters and receptors of neuronal membrane, which therefore protects these cells from hypoxia. In this study we evaluated the ability of rTMS to protect neurons from injury due to hypoxia, and its possible interference in the protective effect of hypothermia and we tried to identify some mechanisms that possibly are involved in this phenomenon. Methods: Ischemia model was performed using Gerbil that was subsequently submitted to an evaluation of behavior and memory through passive avoidance task. The rTMS protocol was daily sessions with 25 series of 5 seconds at 25Hz with an interval of 45 seconds between series, for 7 consecutive days, with a total of 21 875 pulses with an intensity of 100% of motor threshold, and being carried through the induction of ischemia soon after the end of the last session, or rTMS after ischemia, in daily sessions with 25 series of 5 seconds at 25Hz with an interval of 45 seconds between series, for 3 consecutive days, starting immediately after surgery. The temperature of 36 °C was maintained during the period of vessel occlusion and subsequent 30 minutes, or 31 °C to 32 °C when in hypothermia. The preparation of the slices had sections of the region involving the hippocampus, stained with hematoxylin and eosin in addition to other preparations, TUNEL and caspase, which aim to evidence the occurrence of apoptosis. Results: Although not statistically significant, animals that received rTMS, apparently had better performance in passive avoidance task especially when applied after ischemia. The hypothermia demonstrated a significant efficiency, both in the histological analysis and in the passive avoidance task, associated or not to applications of rTMS and, in these animals undergoing ischemia during hypothermia, the ones who received rTMS had survival area in hippocampus significantly higher in histological analysis with hematoxylin and eosin. In animals undergone to ischemia during normal temperature, the rTMS has not shown to increase the area of hippocampal cell survival. Conclusions: rTMS (placebo or active, after or before the ischemia) seems to have a positive effect on passive avoidance task. The stimulation procedure appeared to be very traumatic and stressful for the animal, in which a few deaths occurred during the procedure, probably from asphyxiation due to restraint. The rTMS had a significant protective effect only in animals undergoing ischemia during hypothermia, as demonstrated in the histological analysis with hematoxylin and eosin
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