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Zhu, Wenjun. "The role of brain derived neurotrophic factor in multiple sclerosis and the role of fractalkine in multiple sclerosis induced neuropathic pain." Journal of Neuroscience Methods, 2010. http://hdl.handle.net/1993/16675.
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Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease, characterised by demyelination in the central nervous system (CNS). The exact pathophysiology of MS is still unknown but it is believed to be associated with infiltration of T cells and activation of microglia that result in myelin damage leading to neurological deficits including neuropathic pain. Current treatment strategies such as glatiramer acetate have recognized the importance of BDNF in myelin repair. In addition, the proposed role of the chemokine CX3CL1 and its receptor CX3CR1 in the control of microglia activation and leukocyte infiltration place this chemokine in an important position in regulation of MS-induced neuropathic pain. In this research study, the experimental autoimmune encephalomyelitis (EAE) rat model of MS was used to examine the role of BDNF in myelin repair as well as CX3CL1’s role in neuropathic pain. Methods: A total of 66 adult female Lewis rats are divided into 3 experimental groups: naïve control, active control and active EAE. Naïve control animals do not receive any injections. Active control animals receive 2 intraperitoneal injections of pertussis toxin and injections of Freund’s adjuvant and Mycobacterium Tuberculosis. Active EAE animals receive the same regimen administered to active controls plus full inoculation with fatty acid and Guinea pig myelin basic protein. Expressions of BDNF, CX3CL1 and CX3CR1 in a time dependent mansion (day 0, 3, 6, 9, 12 &15) were examined using immunohistochemistry (IHC), ELISA, Western blot, RT-PCR and real time-PCR. Results: There was a significant increase in BDNF, CX3XL1 and CX3CR1 expression of protein and mRNA in DRG at day 12 after induction of MS. The neurons and glial cells were identified to express BNDF, CX3XL1 and CX3CR1 in the spinal cord of EAE animal. Conclusion: The antigenic-induced expression of BDNF within the DRG may represent a key element involved in facilitating central myelin repair. In addition, the chemokine CX3CL1 and its receptor CX3CR1 represent key mediators involved in the development of MS-induced pain.
Keywords: Multiple sclerosis, MS, experimental autoimmune encephalomyelitis, EAE, CX3CL1, CX3CR1, neuropathic pain, myelin repair
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Zuena, Anna Rita. "Lo Stress Prenatale nel ratto come modello di depressione: accertamento della validità predittiva con l'imipramina e studio della neurogenesi dopo trattamento con una nuova molecola, l'agomelatina (S-20098)." Doctoral thesis, La Sapienza, 2005. http://hdl.handle.net/11573/917224.
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Hartmann, Matthias. "Die Freisetzung von BDNF an glutamatergen Synapsen und die Stimulation der Filopodienbildung durch den trunkierten BDNF-Rezeptor TrkB.T1." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965079686.
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Huie, John Russell. "The role of BDNF in spinal learning." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-2824.
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Pichler, Bruno. "Charakterisierung BDNF-induzierter Calciumtransienten in kultivierten Astrozyten." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=98029391X.
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Fayard, Bérengère. "Studies on the binding properties and functional activities of the precursor of BDNF, proBDNF, and of engineered BDNF mutants /." [S.l.] : [s.n.], 2004. http://www.zb.unibe.ch/download/eldiss/04fayard_b.pdf.
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Béjot, Yannick. "Infarctus cérébral et plasticité : focus sur le BDNF." Phd thesis, Université de Bourgogne, 2011. http://tel.archives-ouvertes.fr/tel-00939908.
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La récupération fonctionnelle des patients victimes d'un accident vasculaire cérébral (AVC) ischémique est largement sous-tendue par les propriétés plastiques du cerveau et plus précisément par sa capacité à remodeler les réseaux de neurones épargnés par l'infarctus. Les études réalisées sur différents modèles animaux d'infarctus cérébral s'accordent à montrer que ces changements plastiques sont induits par le BDNF (Brain-Derived Neurotrophic Factor). Aussi, augmenter les taux cérébraux de BDNF est considéré comme une stratégie thérapeutique prometteuse de réduction des déficiences post-AVC. Dans ce contexte, notre travail avait 2 objectifs : 1) chez le rat, identifier les cellules impliquées dans la surproduction de BDNF et évaluer la pertinence de la mesure des taux circulants de BDNF pour estimer les taux de BDNF présents dans le cerveau, 2) chez le patient victime d'un infarctus cérébral, étudier l'efficacité de la fluoxétine sur la récupération motrice à 3 mois, la fluoxétine étant un inhibiteur spécifique de la recapture de la sérotonine commercialisé comme antidépresseur et capable non seulement d'augmenter la production cérébrale de BDNF mais aussi de stimuler la plasticité post-lésionnelle.Les études précliniques ont été réalisées chez le rat soumis à l'embolisation unilatérale du cerveau par un nombre variable de microsphères (en carbone et calibrées à 50 µm) afin de reproduire le large panel de souffrance cérébrale rencontré en clinique. Le BDNF a été mesuré dans le cerveau et dans le sang (plasma et sérum par technique ELISA) avant et après (4, 24h et 8j) embolisation. Nos résultats montrent :- que la production de BDNF est plus intense et plus durable dans l'hémisphère embolisé que dans l'hémisphère non embolisé et que cette production est indépendante du degré d'embolisation, marqueur indirect de la souffrance cérébrale. - que les cellules non-neuronales deviennent une source non négligeable de BDNF en cas d'ischémie, notamment les cellules endothéliales et microgliales avant 24h et les astrocytes au temps 8j.- que les taux circulants et cérébraux de BDNF ne sont pas corrélés mais qu'il existe une corrélation entre le BDNF plasmatique mesuré au temps 4h et le degré d'embolisation.L'étude clinique correspond à un essai randomisé contrôlé en double aveugle comparant la fluoxétine (20mg/j, voie orale, pendant 3 mois et débutée entre 5 et 10j après les premiers symptômes) au placebo chez des patients présentant un déficit moteur modéré à sévère sur l'échelle motrice de Fugl-Meyer (n=59 dans chaque groupe). Nos résultats montrent que l'amélioration de la fonction motrice est meilleure sous fluoxétine que placebo. En conclusion, notre travail montre l'intérêt des médicaments capables d'augmenter le BDNF et la plasticité post-lésionnelle pour améliorer le pronostic clinique de l'AVC et identifie pour la première fois les cellules endothéliales cérébrales comme une cible potentielle de ces médicaments. Il remet également en cause l'idée largement répandue selon laquelle les taux circulants de BDNF varient dans le même sens que les taux cérébraux.
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Kerr, Bradley James. "Novel modulators of central sensitization : BDNF and galanin." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246735.
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Pedard, Martin. "Endothélium, inflammation et cognition : focus sur le BDNF." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI008/document.
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Le BDNF (brain-derived neurotrophic factor) a été découvert dans le cerveau et est largement impliqué dans la neuroplasticité, la mémoire et la cognition via l’activation des récepteurs TrkB (tropomyosin receptor kinase B) neuronaux. Nous avons récemment montré que le système cardiovasculaire contenait autant de BDNF que le cerveau et que le BDNF exogène était capable d’induire une relaxation vasculaire dépendante de l’endothélium. D’autres études ont suggéré que l’activation des récepteurs TrkB endothéliaux par le BDNF était impliquée dans les processus athérosclérotiques. Notre laboratoire soupçonne une interaction étroite entre NO et BDNF endothélial et a même envisagé la possibilité d’une implication du BDNF secrété par l’endothélium des microvaisseaux cérébraux dans la cognition. Les patients souffrant de polyarthrite rhumatoïde (PR), une maladie inflammatoire d’origine auto-immune, sont à risque cardiovasculaire et présentent une altération de la cognition avec notamment un risque plus élevé de dépression. Etonnamment, l’effet de la PR sur le BDNF est peu documenté. Les seules études disponibles rapportent une élévation du BDNF dans le sang et le liquide synovial en cas de PR. Notre hypothèse est qu’une réduction de l’expression endothéliale du BDNF pourrait contribuer au risque cardiovasculaire et au déficit cognitif associés à la PR. Ainsi, dans notre travail, nous avons étudié le BDNF vasculaire et cérébral et son récepteur TrkB sur le modèle rat d’arthrite induite à l’adjuvant.Nos principaux résultats montrent que l’arthrite conduit à 1) une réduction des taux aortiques de BDNF indépendamment de la sévérité des symptômes inflammatoires mais dépendante de la fonction endothéliale, 2) une diminution des taux cérébraux en BDNF indépendamment de la sévérité des symptômes inflammatoires mais en lien avec la fonction endothéliale, 3) une diminution de l’expression du BDNF et de son récepteur TrkB activé au niveau tant neuronal qu’endothélial dans les régions cérébrales impliquées dans la cognition, 4) une corrélation positive entre l’expression du BDNF par l’endothélium vasculaire et l’expression neuronale des TrkB activés, 5) une absence de corrélation entre les taux sériques de BDNF et ses taux cérébraux ou vasculaires mais en revanche l’existence d’une corrélation positive entre les taux sériques de BDNF et l’inflammation qu’elle soit clinique ou biologique.L’ensemble de ces données est en faveur de l’hypothèse selon laquelle le BDNF endothélial pourrait être impliqué dans le risque athérosclérotique et le déficit cognitif associé à l’arthrite. L’inflammation doit être considérée comme un facteur confondant lorsque les taux circulants de BDNF sont utilisés comme un reflet des taux présents dans le cerveauBDNF (brain-derived neurotrophic factor) has been discovered in the brain and is widely implicated in neuroplasticity, memory and cognition through the activation of neuronal TrkB (tropomyosin receptor kinase B) receptors. We have recently shown that the cardiovascular system contained as much BDNF as the brain and that exogenous BDNF was able to induce endothelium-dependent vascular relaxation. Other studies have suggested that activation of endothelial TrkB receptors by BDNF is involved in atherosclerotic processes. Our laboratory suspects a close interaction between endothelial NO and BDNF and has even considered the possibility of involvement of BDNF secreted by cerebral microvessel endothelium in cognition. Patients suffering from rheumatoid arthritis (RA), an inflammatory disease of autoimmune origin, are at risk of cardiovascular disease and have an impairment of cognition, including a higher risk of depression. Surprisingly, the effect of RA on BDNF is poorly documented. The only available studies report an increase of BDNF in the blood and synovial fluid in RA. Our hypothesis is that a reduction in endothelial expression of BDNF may contribute to the cardiovascular risk and cognitive deficit associated with RA. Thus, in our work, we studied vascular and cerebral BDNF and its TrkB receptor on the rat model of adjuvant-induced arthritis.Our main findings show that arthritis leads to 1) a decrease in BDNF levels in aortas independently of the severity of inflammatory symptoms but dependent on endothelial function, 2) a decrease in brain BDNF levels independent of the severity of inflammatory symptoms, but link with endothelial function, 3) a decreased expression of BDNF and its activated TrkB receptor at both neuronal and endothelial levels in the brain regions involved in cognition, 4) a positive correlation between endothelial expression of BDNF and neuronal expression of activated TrkB, 5) a lack of correlation between serum BDNF levels and its cerebral or vascular levels, but on the other hand the existence of a positive correlation between serum BDNF levels and inflammation, whether clinical or biological.All of these data support the hypothesis that endothelial BDNF may be involved in atherosclerotic risk and cognitive impairment associated with arthritis. Inflammation should be considered as a confounding factor when circulating levels of BDNF are used as a reflection of levels present in the brain
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Quirié, Aurore. "BDNF cérébral et cardiovasculaire : effet de l'activité physique." Thesis, Dijon, 2013. http://www.theses.fr/2013DIJOS073.
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La pratique régulière d’une activité physique (AP) est un important message de santé publique tant pour ces bénéfices cardiovasculaires que cérébraux. Par ailleurs, la rééducation par le mouvement et notamment l’exercice sur tapis roulant est de plus en plus utilisée pour accélérer la récupération après un accident vasculaire cérébral (AVC). Il est admis que l’AP impacte positivement le fonctionnement cérébral via l’augmentation des taux de BDNF (brain-derived neurotrophic factor) dans le cerveau et que son bénéfice cardiovasculaire est à relier à une modification du phénotype endothélial. Dans un premier temps, nous avons mis au point le dosage par Western blotting du proBDNF et du BDNF mature (BDNFm) ainsi que les techniques immunohistochimiques permettant de localiser le BDNF à l’étage cellulaire. Dans un second temps, nous avons comparé l’effet d’une AP (tapis roulant, 30min/j, 18m/min, 7 jours consécutifs) sur le métabolisme et la localisation du BDNF chez des rats sains versus soumis à une ischémie cérébrale focale. Dans un dernier temps, nous nous sommes intéressés à l’expression du BDNF cardiovasculaire chez des rats normo- ou hypertendus, sédentaires ou soumis au modèle d’AP précédent. Les principaux résultats montrent que 1) l’AP augmente les taux de proBDNF et de BDNFm aussi bien dans le cerveau (neurones et cellules endothéliales) que dans le système cardiovasculaire (endothélium vasculaire et cardiaque), 2) l’ischémie cérébrale n’entrave pas les effets cérébraux de l’AP sur le BDNFm, 3) l’expression endothéliale (cœur, aorte, artère coronaire) du BDNF est moindre en cas d’hypertension, 4) la synthèse et la sécrétion de BDNF par des cellules endothéliales en culture augmentent lorsque les cellules sont soumises à des contraintes de cisaillement, 5) le BDNF exerce un effet vasodilatateur sur le modèle d’aorte isolée. En conclusion, notre travail montre qu’il est possible de sélectionner, chez des rats sains, des protocoles d’AP capables d’augmenter la neuroplasticité dépendante du BDNF chez des rats ischémiés. Il identifie également le BDNF d’origine endothéliale comme un marqueur potentiel de la fonction endothéliale et un acteur jusque-là ignoré des changements neuroplastiques induits par l’APThe regular practice of physical activity is an important message for public health as it has both cardiovascular and brain benefits. Furthermore, rehabilitation programs involving movement especially the treadmill exercise are being used increasingly to accelerate post stroke recovery. It is recognised that the physical activity has a positive impact on brain function through increased levels of BDNF (brain-derived neurotrophic factor) in the brain and that its cardiovascular benefit is connected to a change in endothelial phenotype. As a first step, we developped the dosage by Western blotting of proBDNF and mature BDNF (mBDNF) and the immunohistochemical techniques in order to localise BDNF in the cell floor. As a second step, we compared the effect of physical activity (treadmill exercise, 30min/d, 18m/min, 7 consecutive days) on the metabolism and localisation of BDNF in healthy rats versus rats subjected to focal cerebral ischemia. As a final step, we looked into the expression of cardiovascular BDNF in normotensive or hypertensive rats, sedentary or subjected to the same physical activity. The main results show that 1) physical activity increases the levels of proBDNF and mBDNF in both brain (neurons and endothelial cells) and cardiovascular system (heart and vascular endothelium), 2) cerebral ischemia does not change the cerebral effects of physical activity on mBDNF, 3) endothelial expression (heart, aorta, coronary artery) of BDNF is reduced in the presence of hypertension, 4) the synthesis and secretion of BDNF by endothelial cells in culture increase when the cells are subjected to shear stress, 5) BDNF has a vasodilatator effect on the isolated aorta model. In conclusion, our work shows that it is possible to select, in healthy rats, protocols of physical activity that are able to increase the BDNF-dependent neuroplasticity in ischemic rats. It also identifies endothelial BDNF as a potential marker of endothelial function as well as a potential contributor of physical activity-induced neuroplasticity
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Langlois, Anaïs. "Rôle du BDNF dans le développement des synapses GABAergiques de l'hippocampe de rat." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4089/document.
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Le cerveau immature est le siège de processus développementaux qui permettent de passer d'une structure primitive à un réseau mature et fonctionnel. L'activité synaptique spontanée générée dans le système nerveux en développement joue un rôle fondamental dans ces processus. Un des principaux moyens par lesquels cette activité peut être traduite en changement phénotypique au niveau neuronal est la sécrétion de neurotrophines. Les neurotrophines sont sécrétées par les neurones et contrôlent toutes les étapes du développement neuronal. Dans l'hippocampe en développement, la neurotrophine principale est le BDNF (brain derived neurotrophic factor). Cette protéine est synthétisée sous forme immature, le proBDNF, dont le rôle est encore méconnu. Durant ma thèse, j'ai montré que le BDNF exerce un contrôle bidirectionnel sur l'efficacité des synapses GABAergiques en développement. La polarité de la plasticité est déterminée par le type d'activité endurée par les neurones et la forme sous laquelle le BDNF est présenté à ces derniers. J'ai ainsi décrit une séquence développementale qui pourrait s'inscrire dans les processus développementaux permettant la maturation du réseau GABAergique dans l'hippocampe de ratThe immature brain is the place of developmental processes that allow the switch from a primitive structure to a mature and functional network. Spontaneous synaptic activity generated in the developing nervous system plays a fundamental role in these processes. One of the principal ways this activity is translated into phenotypical changes at the neuronal level is the secretion of neurotrophins. Neurotrophins are secreted by neurons and control each step of neuronal development. In the developing hippocampus, the major neurotrophin is BDNF (brain derived neurotrophic factor). This protein is synthetized under an immature form, proBDNF, which role is still poorly known. During my thesis, I showed that BDNF exerts a bidirectional control on the efficacy of developing GABAergic synapses, which polarity is set by the type of activity endured by neurons and the form of BDNF that is presented to them. I described a developmental sequence which could be a part of the developmental processes allowing the maturation of the GABAergic network in the developing rat hippocampus
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Cagni, Fernanda Carvalho. "Rela??o do polimorfismo BDNF val66met e n?veis perif?ricos de BDNF com a doen?a de Parkinson e sua sintomatologia." Universidade Federal do Rio Grande do Norte, 2015. http://repositorio.ufrn.br/handle/123456789/20172.
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As doen?as neurodegenerativas s?o objeto frequente de estudo devido ao n?mero crescente de casos associados ao processo de envelhecimento populacional e pelo impacto que causam na qualidade de vida dos indiv?duos. A doen?a de Parkinson (DP) ? a segunda doen?a neurodegenerativa mais frequente. Apesar da sua etiologia ainda n?o ser completamente conhecida, sabe-se que a mesma ? causada por fatores ambientais e gen?ticos. Assim, a investiga??o dos fatores etiol?gicos e os mecanismos respons?veis pelas altera??es que levam a DP podem contribuir para o seu diagn?stico e preven??o. Uma poss?vel associa??o entre DP e o polimorfismo comum do Fator Neurotr?fico Derivado do C?rebro (BDNF) G196A (Val66Met) tem sido sugerido por diferentes estudos com resultados contrastantes. Por esse motivo, o objetivo deste estudo ? verificar se o polimorfismo BDNF Val66Met confere susceptibilidade a DP em uma amostra de pacientes brasileiros e se isso implica em quaisquer altera??es no n?vel de BDNF em sangue total e na manifesta??o de sintomas. A amostra foi constitu?da de pacientes acompanhados pelo servi?o de neurologia do Hospital Universit?rio Onofre Lopes (HUOL) e controles saud?veis (CTRL). Os aspectos motores da DP foram avaliados pela Escala de Hoehn e Yahr (HY), Unified Parkinson?s Disease Rating Scale (UPDRS) e Escala de Atividades Di?rias de Schwab e England (SE). Para a avalia??o dos aspectos n?o-motores foram utilizados os instrumentos: Bateria de Avalia??o Frontal (BAF), Mini Exame do Estado Mental (MEEM), Invent?rio de Depress?o de Beck (IDB) e o Invent?rio de Ansiedade de Beck (IAB). Amostras de sangue foram coletadas para a genotipagem do polimorfismo Val66Met e mensura??o da concentra??o de BDNF em sangue total. Como esperado, os pacientes com DP apresentaram pior desempenho na avalia??o motora, cognitiva e emocional. A distribui??o dos alelos entre os grupos n?o foi significativamente diferente, por?m o gen?tipo A/G foi associado significativamente como protetor para a DP. O gen?tipo G/G, por sua vez, foi associado significativamente com o desenvolvimento de depress?o e ansiedade em pacientes com DP. No entanto, as concentra??es de BDNF n?o foram diferentes entre os gen?tipos ou grupos. Este ? o primeiro estudo de associa??o gen?tica desse polimorfismo com a DP no Brasil e o primeiro que associou o heterozigoto A/G com prote??o contra a DP.
Neurodegenerative diseases are frequently studied due to the increasing number of cases associated with the populational ageing and to the impact on the conditions on the quality of life. Parkinson?s disease (DP) is the second most frequent neurodegenerative disease. Despite the fact that its etiology is not completely understood, it is known that DP is caused by environmental and genetic factors. Thus, the investigation of etiologic factors and mechanisms responsible for the changes that lead to DP may help early diagnostic and prevention. A possible association between DP and the common polymorphism of Brain Derived Neurotrophic Factor (BDNF) G196A (Val66Met) has been suggested by different studies with contrasting results. For this reason, the aim of this study is to investigate if the BDNF Val66Met polymorphism is related to susceptibility to DP in a cohort of Brazilian patients. Additionaly, we verify if the presence of the polymorphism implies in alterations in the BDNF whole blood concentrations, as well as variations in symptomatology. The sample comprised Brazilian patients accompanied by the neurology service of the Onofre Lopes University Hospital (HUOL) and healthy controls (CTRL). The motor aspects of DP were evaluated by Hoehn e Yahr Scale (HY), Unified Parkinson?s Disease Rating Scale (UPDRS) and Schwab & England Scale (SE). For the evaluation of non-motor symptoms were used the following instruments: Frontal Assessment Battery (BAF), Mini-Mental State Examination (MEEM), Beck Depression Inventory (IDB) and the Beck Anxiety Inventory (IAB). Blood samples were collected for BDNF Val66Met polymorphism genotyping and BDNF whole blood measurement. As expected, DP patients performed worse in motor, cognitive and emotional battery of questionnaires. Alleles distribution between DP and CTRL was not significantly different, but the A/G genotype was significantly associated with a protector factor for DP. In contrast, the G/G genotype was significantly associated with depression and anxiety development in DP patients. However, BDNF concentrations were not different between genotypes or groups. This is the first study of genetic association of this polymorphism with DP in Brazilian subjects and the first one that associate A/G genotype with protection against DP.
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Breitkopf, Oliver. "Variationen im BDNF-Gen im Zusammenhang mit kognitiven Phänotypen." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-93595.
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Bourakkadi, Zarrouki Driss. "Die Wirkung des BDNF-Polymorphismus auf trankraniell induzierte Neuroplastizität." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://hdl.handle.net/11858/00-1735-0000-000D-F681-8.
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Nylocks, Karin Maria. "Influence of the BDNF Val66Met Polymorphism on Emotion Flexibility." Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1479816492607729.
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Kim, Sun. "HAPLOINSUFFICIENCY OF RAI1 AND ITS EFFECT ON BDNF EXPRESSION." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/165.
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Smith-Magenis Syndrome (SMS) [OMIM, #182290] is a congenital anomaly and mental retardation (MCA/MR) syndrome associated with deletion of chromosome17p11.2 [1]. The clinical phenotype has been well described and includes minor craniofacial anomalies, self-injurious behaviors as well as sleep disturbances, speech delays, and obesity [1,2,3]. The incidence of SMS is estimated to be ~ 1:15,000 - 25,000 births [2,6]. Among SMS patients, ~90% are comprised of 17p11.2 deletions, while ~10% have RAI1 mutations [8]. All 17p11.2 deletions associated with SMS include RAI1 deletion [10]. RAI1 is thought to function as a transcriptional factor although its cellular role is still unclear. First, in order to better understand the role of RAI1 as a transcriptional factor and its relation to SMS, we confirmed that RAI1 regulates BDNF within an intronic region. This sequence was further narrowed down by utilizing the luciferase reporter assay. This test confirmed what was previously found using ChIP-chip assay and microarray analysis of Rai1+/- mice hypothalami. Next, in order to evaluate the role of Bdnf, an ampakine drug was administered to the Rai1+/- mouse model. A mouse model is a powerful tool for studying a specific gene. Rai1+/- mice exhibit the SMS phenotypes of obesity, craniofacial abnormalities, reduced pain sensitivities, seizures and others. Many physical, neurological, and behavioral tests were performed on the mice to see if any of the phenotypes can be rescued. Interestingly, twice-daily injections of ampakine CX1837 restored the pain sensitivities in Rai1+/- mice. The hot plate data suggest that BDNF potentially has a role in regulating the SMS phenotype of decreased pain sensitivity. In order to evaluate other genes that are altered as a result of the CX1837 ampakine drug, the whole brain's global gene expression was evaluated via microarray analysis. Two potential pain-related genes were identified to be upregulated due to drug administration, which could account for the pain phenotypes observed. One of the genes upregulated in treated mice was Osm, which is interesting because Osm is responsible for pain sensitivity. Further analysis is needed to confirm that an ampakine drug can potentially be used to treat SMS patients.
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Breitkopf, Oliver. "Variationen im BDNF-Gen im Zusammenhang mit kognitiven Phänotypen." kostenfrei, 2008. http://edoc.ub.uni-muenchen.de/9359/.
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GUARAN, Valeria. "NANOTECHNOLOGIES AND PHAGE DISPLAY: SELECTION OF PEPTIDES MIMICKING BDNF." Doctoral thesis, Università degli studi di Ferrara, 2009. http://hdl.handle.net/11392/2389198.
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Brain derived neurotrophic factor is a neurotrophin of vital importance for
neuron survival.
It may therefore be of great help to people affected by sensorineural
hearing loss and cochlear implant users, as it has already been
demonstrated that it maintains neuronal cells alive and this proved to be
necessary for the device to work.
The issue with its clinical application is related to its large size that makes
it difficult to deliver.
In this thesis I took on one of the tasks of a European project.
The objective of the Nanoear project is the creation of multifunctional
nanoparticles that could be used as drug carriers for a target delivery in the
inner ear.
The final aim is to find a substitute for BDNF protein, able to mimic its
action but small enough to be attached to the nanoparticles and carry them
to their target in the inner ear.
The best method to obtain small peptides with these features is the phage
display. This technique allows selection of a pool of specific peptides
binding specifically to an immobilized target.
In collaboration with an English company involved in the project as well,
we worked to set all the parameters in order to make the phage display for
this project feasible.
As our goal was attaining BDNF mimetic peptides our target had to be its
functional receptor, TrkB.
Starting from a polyA+ RNA library from adult human brain we could get
the genes coding for TrkB and BDNF and follow all the process up to the
expression of the two proteins in bacteria and in eukaryotic cells, as well.
In order to include into nanoparticles the most specific peptides many
approaches for the phage display were taken into consideration and
experimented on.
This technique was in fact performed in vivo on guinea pigs and all the
parameters were set for different trials in vitro either on eukaryotic cells or
on the specific binding domain purified from bacteria.
Therefore the results and the data obtained in this study can lead to a new
generation of drug with great clinical potential.
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BIMBI, GIORGIA. "Local transport and translation of BDNF following synaptic potentiation." Doctoral thesis, Università degli Studi di Trieste, 2023. https://hdl.handle.net/11368/3042423.
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The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in neuronal survival and neurite out-growth, synaptogenesis and synaptic plasticity. BDNF mRNA can be transported in neuronal dendrites in an activity-dependent manner in particular, following seizures but also in response to antidepressants or physical activity. At present, a clear demonstration that BDNF mRNA is locally transported and translated at activated synapses in response to the induction of long-term potentiation (LTP) is still lacking. Here, we study the dynamics of BDNF mRNA trafficking during neuronal plasticity induced by chemical-LTP. The project explores the two hypotheses of selective vs. non-selective dendritic transport of BDNF transcripts after synaptic potentiation and the related methodological constrains using the MS2 system for mRNA visualization in living neurons.The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in neuronal survival and neurite out-growth, synaptogenesis and synaptic plasticity. BDNF mRNA can be transported in neuronal dendrites in an activity-dependent manner in particular, following seizures but also in response to antidepressants or physical activity. At present, a clear demonstration that BDNF mRNA is locally transported and translated at activated synapses in response to the induction of long-term potentiation (LTP) is still lacking. Here, we study the dynamics of BDNF mRNA trafficking during neuronal plasticity induced by chemical-LTP. The project explores the two hypotheses of selective vs. non-selective dendritic transport of BDNF transcripts after synaptic potentiation and the related methodological constrains using the MS2 system for mRNA visualization in living neurons
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Morzelle, Maressa Caldeira. "Efeito neuroprotetor da casca de romã (Punica granatum)." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/11/11141/tde-30092016-182359/.
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A doença de Alzheimer é uma afecção crônica degenerativa que não possui tratamento até o momento. O uso de alimentos funcionais como a romã na prevenção e/ou tratamento de doenças neurodegenerativas têm sido amplamente pesquisados. Diante disto, o presente trabalho teve como objetivo avaliar a quantidade de compostos bioativos (antocianinas, compostos fenólicos e flavonoides), atividade anticolinesterásica e a capacidade antioxidante in vitro e on line dos extratos de polpa e casca de romã e posteriormente estudar o possível efeito neuroprotetor de micropartículas obtidas a partir do extrato da casca de romã em um animal submetido a infusão crônica de peptídeo β-amilóide. O extrato de casca de romã apresentou maior teor de antocianinas, compostos fenólicos, flavonoides e atividade antioxidante in vitro e on line do que o extrato da polpa. Na análise de compostos não voláteis pela técnica de GC-MS foram identificados 38 compostos no extrato da casca e 37 da polpa de romã, sendo o ácido gálico a principal substância detectada. Foram encontrados no total 13 compostos no extrato de casca e 8 no extrato de polpa de romã que apresentaram atividade antioxidante pelo método HPLC-ABTS on line. A punicalagina, epicatequina e ácido gálico foram os compostos determinantes para a atividade antioxidante em ambos os extratos. O extrato da casca de romã apresentou atividade anticolinesterásica superior ao da polpa. Estes resultados, em conjunto, indicaram um possível potencial da casca de romã como um agente neuroprotetor na doença de Alzheimer. Para estudar o possível efeito neuroprotetor do extrato da casca de romã foram utilizados camundongos C57BL/6 cronicamente infundidos com peptídeo βA1-42 e/ou veículo através de mini-bombas osmóticas durante 35 dias e foram avaliados biomarcadores e alterações comportamentais. Micropartículas de extrato de casca de romã, produzidas em spray dryer, foram diluídas em água e administradas na dose de 800 mg de casca de romã/kg de animal/dia. A memória espacial foi avaliada em labirinto de Barnes e uma redução no número de erros para encontrar a caixa de escape foi verificada nos animais tratados com micropartículas de casca de romã e nos animais do grupo controle, mas não nos animais do grupo βA. A atividade da acetilcolinesterase, neurotrofina BDNF, TNF-α e a enzima SOD foram avaliadas no hipocampo, córtex e soro dos animais. A peroxidação lipídica foi avaliada no fígado dos animais. Como a casca de romã não é comumente consumida foram dosados marcadores de dano isquêmico hepático. O consumo de micropartículas de casca de romã promoveu uma redução do acumulo de placas amiloides, aumento da expressão de neurotrofinas, redução da atividade da enzima acetilcolinesterase, redução da peroxidação lipídica e da citocina pró-inflamatória TNF-α em animais infundidos com peptídeo β-amilóide. O consumo das microcáspulas de casca de romã não acarretou nenhum tipo de lesão hepática. No geral, verificou-se que os compostos presentes na casca de romã podem apresentar um efeito neuroprotetor em animais submetidos a infusão crônica de peptídeo β-amilóide.Alzheimer\'s disease is a chronic and degenerative condition that have no treatment until now. The research of functional foods such as pomegranate for the prevention and/or treatment of many conditions, including neurodegenerative diseases, is increasing year after year. The amount of bioactive compounds (anthocyanins, phenolic compounds and flavonoids), acetylcholinesterase activity and antioxidant capacity in vitro and on line of pomegranate peel and pulp extracts were evaluated. Pomegranate peel extract has higher content of anthocyanins, phenolic compounds, flavonoids and antioxidant activity in vitro and on line than pulp. The analyses of the profile of non-volatile compounds identified 38 compounds in the peel and 37 in the pulp. The gallic acid was main compound detected. Pomegranate peel showed 13 compounds with antioxidant activity by the HPLC-ABTS method online and pulp showed eight compounds. Punicalagin, Gallic acid and epicatechin were determinants for the antioxidant capacity of the aqueous-alcoholic extract of pomegranate. Pomegranate peel extract had greater anticholinesterase activity than pulp. These results together indicated a possible potential of pomegranate peel as a neuroprotective agent in Alzheimer\'s disease. This research had as objective to study the possible neuroprotective effect of pomegranate peel on an animal model of the Alzheimer\'s disease. For that purpose, mice model of Alzheimer\'s disease were used and biomarkers and behavioral changes were evaluated. C57BL/6 mice were chronically infused with βA1-42 peptide and/or vehicle by mini - osmotic pumps during 35 days. Microparticles of pomegranate peel extract, produced by spray drying, were diluted in water and administered at a dose of 800 mg of pomegranate peel/ kg animal/day. The spatial memory was evaluated in the Barnes maze and a reduction of the errors to find the scape box was verified in animals treated with the PPE, as observed in the Control group, but not in th Aβ group. The activity of acetylcholinesterase, neurotrophin BDNF, TNF-α and SOD were measured in the hippocampus, cortex and serum. Lipid peroxidation was evaluated in the liver. As the pomegranate peel is not commonly consumed, biomarkers of liver ischemic damage were measured. Pomegranate peel consumption promoted a reduction of amyloid plaques, increasing neurotrophin expression, reduction in a AChE activity, reduced lipid peroxidation and reduced TNF-α in animal models of Alzheimer\'s disease. The consumption of pomegranate peel did not cause liver injury. In general, pomegranate peel showed a neuroprotective effect on animal models of the Alzheimer\'s disease.
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Hinderberger, Philipp. "The Effect of Serum BDNF Levels on Central Serotonin Transporter Availability in Obese Versus Non-Obese Adults: A [11C]DASB Positron Emission Tomography Study." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-214753.
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Background: Serotonin (5-HT) and its neurotrophic support system, specifically brain-derived neurotrophic factor (BDNF), are thought to modulate energy homeostasis and susceptibility to obesity. Moreover, a polymorphism (5-HTTLPR) in the serotonin reuptake transporter (5-HTT) gene impairs its transcription, thereby altering serotonergic tone and potentially contributing to such susceptibility. This study aims to investigate the effect of BDNF, biallelic 5-HTTLPR, and central in-vivo 5-HTT availability in highly obese versus non-obese subjects using positron emission tomography (PET) and 5-HTT selective [11C]DASB.
Methods: Thirty-eight subjects, 24 obese (body mass index, BMI, >35 kg/m2), otherwise mentally and physically healthy, and 14 non-obese (BMI ≤ 25 kg/m2), age- and sex-matched healthy controls were included in this study. Parametric images of binding potential were generated from PET data. Central 5-HTT availability, 5-HTTLPR genotype, and serum BDNF concentrations were analyzed, first in a volume of interest, then in a voxel-wise manner.
Results: Overall, our results showed an absence of a linear correlation between BDNF, in-vivo central 5-HTT availability, and body mass index (BMI). 5-HTTLPR genotyping revealed BDNF and hippocampal 5-HTT availability to be negatively correlated (r = −0.57, p = 0.007) in long allelic homozygotes. However, obese subjects exhibited opposing effects of BDNF levels on 5-HTT availability in the nucleus accumbens (NAcc) relative to our non-obese controls.
Conclusions: Our data did not confirm an overall correlation between serum BDNF, in-vivo central 5-HTT availability, 5-HTTLPR, and BMI. However, there is evidence that serotonergic tone linked to BDNF, specifically in the NAcc, is involved in the pathophysiology of obesity, although this needs further exploration over a wide range of reward-related eating behaviors.
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Breiter, Sarah [Verfasser], Thomas [Gutachter] Mittmann, and Georg [Gutachter] Zoidl. "Die Rolle des neurotrophen Faktors BDNF für läsionsinduzierte Plastizität im visuellen Kortex der BDNF (+/-) Maus / Sarah Breiter ; Gutachter: Thomas Mittmann, Georg Zoidl ; Medizinische Fakultät." Bochum : Ruhr-Universität Bochum, 2011. http://d-nb.info/1202605044/34.
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Sampathkumar, Charanya [Verfasser]. "Interplay between MeCP2 and BDNF in Rett Syndrome / Charanya Sampathkumar." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1123572259/34.
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Slack, Sarah Elisabeth. "Mechanisms of BDNF-modulated synaptic plasticity in the spinal cord." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407337.
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Cornélio, Daniela Baumann. "Neuropeptídeos GRP e BDNF como alvos moleculares em neoplasias femininas." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/72309.
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Receptores de neuropeptídeos e neurotrofinas constituem importantes alvos moleculares no câncer. Fatores de crescimento como o peptídeo liberador da gastrina (GRP) e fator neurotrófico derivado do cérebro (BDNF) estão envolvidos na proliferação celular e progressão do câncer, influenciando na invasão local, angiogênese, metastatização e apoptose. O receptor de GRP (GRPR) tem sido identificado em muitos tumores humanos, mas até o presente trabalho não havia nenhuma informação na literatura quanto à sua expressão em câncer cervical. Nosso estudo inicial demonstrou pela primeira vez a expressão aberrante em GRPR em displasias e câncer do colo uterino, levantando a hipótese de que este receptor poderia estar implicado no processo carcinogênico destes tumores. Para explorar o papel de GRPR como um biomarcador de lesões de colo uterino, em nosso segundo estudo objetivamos avaliar o potencial diagnóstico da detecção de GRPR por imunocitoquímica, técnica que também não havia sido previamente descrita. Verificamos que este receptor foi fortemente associado com displasia e neoplasia cervical invasora. Além disso, o exame demonstrou elevada acurácia para lesões classificadas como células escamosas atípicas de significado indeterminado (ASCUS). Com base nestes resultados, concluímos que a expressão de GRPR por imunocitoquímica pode ser considerada como um método adicional para a detecção de lesões cervicais. Estudos prévios indicam que o bloqueio de GRPR ou do receptor tropomiosina quinase B (TrkB) pode ter efeito antiproliferativo em células de câncer. Neste trabalho mostramos que a ativação do GRPR pode reduzir, ao passo que o bloqueio pode aumentar a viabilidade de células de câncer de ovário, mama e colo uterino. Além disso, demonstramos que a inibição TrkB reduz a viabilidade destas células, sendo que o tratamento com BDNF aumentou a viabilidade de células de ovário. Os resultados obtidos reforçam o conhecimento de que as sinalizações GRP/GRPR e BDNF/TrkB regulam a viabilidade de células de câncer. Ainda mais importante, fornecem a primeira evidência de que, sob certas condições, a ativação de GRPR pode inibir, em vez de estimular, células neoplásicas de mama, ovário e colo uterino.Neuropeptide and neurotrophin receptors are increasingly important molecular targets in cancer. Growth factors as the gastrin-releasing peptide (GRP) and brain-derived neurotrophic factor (BDNF) are involved in cell proliferation and cancer progression, enhancing local invasion, angiogenesis, distant metastasis and apoptosis. The GRP receptor has been identified in many human malignancies, but no information regarding its expression in cervical cancer was found in the literature. Considering that cervical cancer is a very important cause of morbidity and mortality worldwide, we aimed to evaluate the GRPR expression profile in preinvasive and invasive cervical lesions. Our initial study demonstrated for the first time the aberrant GRPR expression in human cervical dysplasia and cancer, raising the hypothesis that GRPR could be implicated in the carcinogenic process of cervical tumors. To further exploit GRPR as a biomarker, in our second study we aimed to evaluate the diagnostic potential of GRPR immunocytochemistry in detecting cervical dysplasia and invasive cancer. This was the first immunocytochemical evaluation of GRPR expression in cervical epithelial cells. This receptor was strongly associated with cervical dysplasia and invasive cancers. Additionally, GRPR immunosignaling showed high accuracy in detecting dysplasias in cells classified as atypical squamous cells of undetermined significance (ASCUS). Based on these results, we concluded that immunocytochemistry for GRPR may be regarded as a valuable method for early detection of cervical intraepithelial neoplasia. Previous studies have indicated that compounds that act by blocking gastrin-releasing peptide receptors (GRPR) or tropomyosin receptor kinase B (TrkB) receptors can display antiproliferative activities against cancer cells. Here we show that GRPR activation can reduce, whereas its blockade can increase, the viability of breast, ovarian, and cervical cancer cell lines. In addition, we demonstrate that TrkB inhibition reduces the viability of these cells and BDNF increases the viability of ovarian cells. The results support the view that GRPR and BDNF/TrkB signaling regulate cancer cell viability. Most importantly, the findings provide the first evidence that, under certain conditions, GRPR activation can inhibit, rather than stimulate, breast, ovarian and cervical cancer cells.
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Payne, Andrew Jordan. "The Effects of Alcohol on BDNF and CD5 Dependent Pathways." BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8638.
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Alcohol represents the third leading cause of preventable death in the United States. Yet, despite its prevalent role in impeding human health, there is much to understand about how it elicits its effects on the body and how the body and brain change when an individual becomes physiologically dependent upon alcohol. The work presented herein represents an effort to elucidate the acute and chronic effects of alcohol on the nervous system. We investigate two specific protein pathways and their role in alcohol’s effects on the body. The first begins with brain-derived neurotrophic factor (BDNF), which acts on TrkB, and ends with KCC2. We demonstrate that BDNF expression is increased in the VTA during withdrawal from chronic but not acute alcohol exposure and that this increase persists for at least seven days. Concomitantly, we demonstrate that the activation of GABAA channels on produces less inhibition of VTA GABA neurons in mice treated with chronic intermittent ethanol exposure than in alcohol naïve mice. This effect likewise persisted for at least seven days. We illustrate that BDNF has no apparent direct effect on VTA GABA neuron firing rate. The second pathway begins with the T cell marker CD5 and ends with the anti-inflammatory cytokine, IL-10. We demonstrate that in a genetic CD5 knockout (CD5 KO) mouse model both alcohol consumption as well as the sedative properties of alcohol are reduced. Since CD+ B cells secrete more IL-10 than CD5- B cells, we also demonstrate the effects of IL-10 on VTA neurons. We show that IL-10 has direct effects on VTA dopamine (DA) neurons by increasing their firing activity. We relatedly illustrate that IL-10 produces an increase in DA release in the nucleus accumbens (NAc). However, contrary to our hypotheses, we show that IL-10 produces conditioned place aversion rather than conditioned place preference in a place conditioning paradigm, suggesting that IL-10 might mediate pain-induced secretions of DA. Collectively, these results suggest two potential therapeutic targets to reduce alcohol consumption that need further validation. They also suggest a novel mechanism for the sedative effects of alcohol at moderate and high doses.
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Kirby, Seth, Katherine C. Burgess, L. A. Beuttel, Daniel J. Peterson, C. A. Bradley, Meng-Yang Zhu, Matthew I. Palmatier, and Russell W. Brown. "Nucleus Accumbens BDNF Overexpression Alters the Behavioral Response to Nicotine." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/967.
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Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in synaptic differentiation, growth, and maintenance. Increases in BDNF have been shown in substance abuse and decreases in BDNF have been shown in response to stress and major depressive disorder (MDD). We analyzed the effects of BDNF upregulation via lentivirus on Pavlovian conditioned approach (PCA), behavioral sensitization, and nicotine self-administration in rats. Lentiviral-mediated expression cassettes, with dual promoters to drive the BDNF gene and the reporter gene were constructed according to the manufacturer’s instruction and surgically injected into the nucleus accumbens (Nac), the primary brain area that mediates drug reward and reinforcement. Rats were allowed to recover for three weeks before behavioral testing commenced. All rats were trained to associate the presentation of a lever and illumination of a stimulus light with delivery of 20% sucrose in a Pavlovian conditioned approach (PCA) task. Head entries into the receptacle where sucrose was delivered (goal tracking) and lever pressing (sign tracking) during the conditioned stimulus (CS) were measured to determine if BDNF over-expression (BDNF+) altered approach to the sign or goal location. Rats in the BDNF+ group made more goal directed behaviors during the CS than sham group. There were no differences in sign tracking and no differences in basal activity. This pattern suggests that BDNF over-expression may increase reward-related learning in a manner specific to goal tracking. Three days after completion of the PCA task, all animals were habituated to a locomotor arena followed by nicotine behavioral sensitization, and were administered nicotine (ip, 0.5 mg/kg free base) or saline every second day for seven days. Results revealed that the BDNF+ group demonstrated enhanced sensitivity to the hypoactive response to nicotine. At day 7, BDNF+ animals demonstrated enhanced behavioral sensitization to nicotine as compared to all other groups, and Sham NIC animals demonstrated sensitization compared to Sham SAL controls. Thus, it appears increasing NAc BDNF expression enhances the behavioral response to nicotine. Animals were then surgically implanted with a jugular catheter and commenced nicotine self-administration. Interestingly, BDNF+ rats demonstrated reduced nicotine self-administration and motivation to obtain nicotine. Global changes in BDNF expression could be a mediating variable in endophenotypes that are more or less susceptible to drug-taking and substance dependence.
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Vaghi, Valentina. "BDNF translational control as a therapeutic target in Rett syndorme." Doctoral thesis, Università degli studi di Trieste, 2011. http://hdl.handle.net/10077/5434.
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2009/2010Rett syndrome (RTT, MIM 312750) is a debilitating neurodevelopmental disorder that manifests in early childhood and affects almost exclusively girls. It 's a genetic disorder and is present worldwide with an estimated average incidence of 1:10,000 / 15,000 newborn girls. RTT is the second leading cause of mental retardation in female often misdiagnosed as autism or an unspecified developmental delay. In its classic version, this disease is caused by mutations in the transcription factor Methyl-CpG binding protein 2 (MeCP2) located on the female X chromosome (Amir et al., 1999). MeCP2 is a transcriptional regulator of many genes, including the neurotrophic factor Brain Derived Neurotrophic Factor (BDNF). BDNF is a member of the neurotrophins family and represents a key molecule for neuronal survival and development, and it is involved in learning and memory processes. BDNF levels significantly increase during the first period of postnatal life till it reaches the threshold necessary for the maturations of neurons with the development of dendrites, axons, dendritic spines and synapses. Recent studies have shown that in transgenic mice, in which MECP2 gene has been inactivated to mimic the symptoms of RTT, the mRNA levels of BDNF are reduced and, in these animals at 6-8 weeks of age, the total content of BDNF protein is reduced by 70%. Furthermore, the overexpression of BDNF in MeCP2-/Y mice leads to an increase in lifespan, improved locomotor deficits and electrophysiological defects, while the deletion of the gene coding for BDNF in the same animals leads to an early onset of the disease symptoms. The main goal of this thesis is to identify a possible drug treatment for the treatment of RTT. The idea is based on the fact that in animal models of RTT there are residual levels of mRNA coding for BDNF and that many drugs, mostly used for the treatment of depression, are able to increase the synthesis of BDNF. In this study we analyzed the residual expression of different BDNF transcripts in human brain and in two models of RTT (the mouse and the cellular model). Using quantitative PCR, we determined the residual expression of BDNF transcripts in post mortem brain samples of RTT patients, using tissues from somatosensory and motor cortex (Broadmann areas 1-5), which are the most affected by the disease. In addition, we determined the expression of BDNF transcripts in the cortex and hippocampus of MeCP2-/Y at different of post-natal ages. Finally, in order to establish a cellular model of disease, we disrupted the expression of MeCP2 gene in human neuroblastoma cell line SHSY-5Y (via RNA interference), and then we measured the expression levels of BDNF transcripts. Using the same cell line we obtained information on the translatability of the different BDNF transcripts through a luminescence assay, based on firefly luciferase as a reporter gene. We observed that in the absence of stimuli, each exon contained the 5'UTR of the BDNF leads to a different level of translation of the reporter gene. We therefore conducted a systematic pharmacological translation of each BDNF transcript to determine what compounds may be used to stimulate the synthesis of BDNF starting from its own specific transcripts. The treatment with serotonin and norepinephrine separately, or with two antidepressants such as desipramine and mirtazapine were found to be most effective in stimulating the BDNF synthesis. These results encourage the planning of future experiments to test the efficacy of existing antidepressant drugs in restoring the compromised BDNF levels in RTT.
La sindrome di Rett (RTT, MIM 312750) è un debilitante disordine neurologico dello sviluppo, che si manifesta nella prima infanzia e colpisce quasi esclusivamente le bambine. E’ una malattia genetica ed è presente in tutto il mondo con una incidenza media stimata di 1:10.000 / 15.000 bambine nate. La RTTè la seconda causa di ritardo mentale femminile spesso erroneamente diagnosticata come autismo o un non specificato ritardo dello sviluppo. Nella sua variante classica, questa malattia è causata da mutazioni nel fattore di trascrizione Methyl-CpG binding protein 2 (MeCP2) localizzato sul cromosoma femminile X (Amir et al., 1999). In condizioni normali MeCP2 è un regolatore della trascrizione di numerosi geni, tra cui il fattore neurotrofico Brain Derived Neurotrophic Factor (BDNF). Il BDNF è un membro della famiglia delle neurotrofine e rappresenta una molecola chiave per la sopravvivenza, lo sviluppo neuronale e i processi di apprendimento e memoria. I livelli di BDNF aumentano significativamente durante il primo periodo di vita postnatale fino a raggiungere la soglia necessaria per lo sviluppo di neuroni maturi con lo sviluppo di dendriti, assoni, spine dendritiche e sinapsi. Studi recenti hanno dimostrato che in topi transgenici in cui il gene MeCP2 è stato inattivato per mimare la sintomatologia della RTT, i livelli di mRNA del BDNF risultano ridotti e, in tali animali, a 6-8 settimane di età il contenuto totale di proteina BDNF è ridotto del 70% rispetto agli animali selvatici. Inoltre, l’overespressione di BDNF in topi privi del gene funzionale per MeCP2 porta a un aumento della durata della vita, a un miglioramento dei deficit locomotori e dei difetti elettrofisiologici, mentre la delezione del gene che codifica per bdnf negli stessi animali porta a una precoce insorgenza dei sintomi della patologia. Lo scopo di questa tesi è individuare un possibile trattamento farmacologico per la cura della RTT. L’idea si basa sul fatto che in modelli animali di RTT sono presenti dei livelli residui dell’mRNA codificante per il BDNF e che sono noti numerosi farmaci, utilizzati per lo più per la terapia della depressione che aumentano la sintesi del BDNF. In questo studio abbiamo analizzato l’espressione residuale dei diversi trascritti del BDNF in cervelli umani RTT e in due modelli di RTT. Mediante PCR quantitativa, abbiamo determinato l’espressione residuale dei trascritti del BDNF in cervelli umani di soggetti normali e affetti da RTT di età comparabile usando tessuti delle aree di Broadmann 1-5 che includono le cortecce somatosensoriali e motorie e che risultano essere le più colpite dalla malattia. Inoltre, abbiamo determinato i livelli dei trascritti del BDNF nella corteccia e nell’ippocampo di topi normali e in topi transgenici con delezione del gene MeCP2 (Bird) a differenti stadi post-natali. Infine, per stabilire un modello cellulare della malattia abbiamo distrutto l’espressione di MeCP2 nella linea cellulare di neuroblastoma umano SHSY-5Y mediante la tecnica dell’RNA interference e misurato l’espressione dei trascritti di BDNF. Utilizzando la stessa linea cellulare abbiamo ottenuto informazioni sulla traducibilità dei diversi trascritti del BDNF grazie a un saggio di luminescenza basato sull’utilizzo della luciferasi come gene reporter. Abbiamo osservato che in assenza di stimoli, ogni esone contenuto al 5’UTR del BDNF determina una diverso livello di traduzione del gene reporter. Abbiamo quindi condotto un’analisi farmacologica sistematica della traduzione di ciascun trascritto di BDNF per determinare quali composti possono essere usati per stimolare la sintesi BDNF partendo da un suo specifico trascritto. La combinazione di serotonina e norepinefrina, che si può ottenere anche mediante trattamento con antidepressivi quali desipramina e mirtazapina, è risultata essere la più efficace nello stimolare la sintesi del BDNF. Questi risultati ci incoraggiano a progettare futuri esperimenti per testare farmaci già esistenti sul mercato farmaceutico usando il modello cellulare ed il modello animale RTT.
XXIII Ciclo
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Montalbano, Alberto. "Synaptic plasticity regulation mediated by BDNF: functional and morphological study." Doctoral thesis, Università degli studi di Trieste, 2012. http://hdl.handle.net/10077/7404.
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2010/2011The long-term potentiation (LTP) represents a widely studied form of synaptic plasticity related to learning and memory processes, which involves a long-lasting strengthening of synaptic connections through changes of their transmission and cytoarchitecture. The induction of LTP is classically achieved by tetanic stimulation of presynaptic components but it is also possible to in- duce chemically a long-term potentiation of the synaptic efficacy, thus enhancing a larger number of synapses compared to electrical stimulation and facilitating the biochemical and morphological study. The first part of this thesis is a methodological study of glycine and tetraethylammonium (TEA) induced chemical LTP (cLTP) in cultured hippocampal cells. Brief glycine (in Mg2+-free) application activate NMDA receptors, whereas TEA blocks of K+ channels inducing a depolariza- tion responsible for Ca2+ influx. Both drugs were briefly superfused and mEPSCs were monitored for all the duration of the experiments (≃60 min). This was considered as a necessary step to detect later the role of the Brain Derived Neurophic Factor (BDNF) in cLTP. Healthy hippocampal cells were dissected from rats of postnatal day 1-2. After a period of 10-12 days in vitro the cells reached optimal density, a typical mature pyramidal neuron morphology, and an extended dendritic arborization which facilitates synaptic contacts. At this stage patch-clamp technique in the whole-cell configuration was used to study the electrophysiological properties of pyramidal hippocampal neurons, able to produce spontaneous electrical activity. cLTP was tested recording miniature excitatory postsynaptic currents (mEPSCs) in voltage-clamp mode focusing on changes in their amplitude and frequency. A significant decrease in mEPSCs inter-event intervals was observed after glycine and TEA application, without significant changes in aptitudes. Therefore 20 min after glycine application an increase (≃ 61.6 %) in mEPSCs frequency was observed. A similar result was obtained also after TEA application (≃ 66 %). Following cLTP we observed also morphological changes such as an increase in density and a remodeling of different classes of dendritic spines. The role of BDNF in this cLTP model was assessed testing by ELISA assay the total BDNF expres- sion on cell lysate and by blocking Tropomyosin Receptor Kinase (Trk) with K252A. A significant increase in BDNF levels (≃ 120 %) was observed 50 min after cLTP induction. A switch from cLTP into cLTD was observed blocking Trk receptors. Moreover, confocal images collected before and after chemical potentiation in the presence of K252A showed a significant reduction (≃10%) in the average spine density both at the proximal and distal level. A significant reduction of the p-TrkB/TrkB ratio, after both gly- and TEA-LTP, was observed in distal dendrites compared to the soma. This therefore suggests a translocation of the activated receptor from periphery to the soma.
XXIV Ciclo
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Wu, Linyan, and wu0071@flinders edu au. "BRAIN DERIVED NEUROTROPHIC FACTOR TRANSPORT AND PHYSIOLOGICAL SIGNIFICANCE." Flinders University. Medicine, 2007. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20071204.113001.
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Neurotrophins are important signaling molecules in neuronal survival and differentiation. The precursor forms of neurotrophins (proneurotrophins) are the dominant form of gene products in animals, which are cleaved to generate prodomain and mature neurotrophins, and are sorted to constitutive or regulated secretory pathway and released. Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the brain development and in the pathogenesis of neurological diseases. In Huntingtons disease, the defective transport of BDNF in cortical and striatal neurons and the highly expressed polyQ mutant huntingtin (Htt) result in the degeneration of striatal neurons. The underlying mechanism of BDNF transport and release is remains to be investigated. Current studies were conducted to identify the mechanisms of how BDNF is transported in axons post Golgi trafficking. By using affinity purification and 2D-DIGE assay, we show Huntingtin-associated protein 1 (HAP1) interacts with the prodomain and mature BDNF. The GST pull-down assays have addressed that HAP1 directly binds to the prodomain but not to mature BDNF and this binding is decreased by PolyQ Htt. HAP1 immunoprecipitation shows that less proBDNF is associated with HAP1 in the brain homogenate of Huntingtons disease compared to the control. Co-transfections of HAP1 and BDNF plasmids in PC12 cells show HAP1 is colocalized with proBDNF and the prodomain, but not mature BDNF. ProBDNF was accumulated in the proximal and distal segments of crushed sciatic nerve in wild type mice but not in HAP1-/- mice. The activity-dependent release of the prodomain of BDNF is abolished in HAP1-/- mice. We conclude that HAP1 is the cargo-carrying molecule for proBDNF-containing vesicles and plays an essential role in the transport and release of BDNF in neuronal cells. 20-30% of people have a valine to methionine mutation at codon 66 (Val66Met) in the prodomain BDNF, which results in the retardation of transport and release of BDNF, but the mechanism is not known. Here, GST-pull down assays demonstrate that HAP1 binds Val66Met prodomain with less efficiency than the wild type and PolyQ Htt further reduced the binding, but the PC12 cells colocalization rate is almost the same between wt prodomain/HAP1 and Val66Met prodomain/HAP1, suggesting that the mutation in the prodomain may reduce the release by impairing the cargo-carrying efficiency of HAP1, but the mutation does not disrupt the sorting process. Recent studies have shown that proneurotrophins bind p75NTR and sortilin with high affinity, and trigger apoptosis of neurons in vitro. Here, we show that proBDNF plays a role in the death of axotomized sensory neurons. ProBDNF, p75NTR and sortilin are highly expressed in DRG neurons. The recombinant proBDNF induces the dose-dependent death of PC12 cells and the death activity is completely abolished in the presence of antibodies against the prodomain of BDNF. The exogenous proBDNF enhances the death of axotomized sensory neurons and the antibodies to the prodomain or exogenous sortilin-extracellular domain-Fc fusion molecule reduces the death of axotomized sensory neurons. We conclude that proBDNF induces the death of sensory neurons in neonatal rats and the suppression of endogenous proBDNF rescued the death of axotomized sensory neurons.
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Janke, Kellie. "Voluntary Wheel Running Alters Brain-Derived Neurotrophic Factor Levels in the Hippocampus of Senescence Accelerated Mice." Bowling Green State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1237829856.
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Riffault, Baptiste. "Plasticité GABAergique et épilepsie : focus sur le proBDNF." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4005/document.
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Le facteur neurotrophique dérivé du cerveau (BDNF) synthétisé sous la forme d'un précurseur (proBDNF) qui peut être clivé pour donner sa forme mature (mBDNF). Le mBDNF et le proBDNF produisent des réponses physiologiques opposées par l'activation de deux classes distinctes de récepteurs transmembranaires : respectivement, le récepteur TrkB et p75NTR. Le ratio mature/pro-BDNF est un élément important impliqué dans la plasticité synaptique, la formation des circuits neuronaux et in fine les fonctions cognitives. Les altérations dans ce clivage peuvent ainsi expliquer l’émergence de conditions pathologiques post-lésionnelles, comme la mort cellulaire induite par un état de mal épileptique. Au cours de ma thèse, j'ai montré que l'altération de la maturation du BDNF in vitro, provoquait, via le récepteur p75NTR, une altération de l’activité GABAergique. Par ailleurs, au cours des crises d'épilepsies, les réponses dépolarisantes et excitatrices du GABA, soutenus par la baisse d’expression et d’activité du co-transporteur KCC2, ont été rapportées. Ainsi, in vivo, j’ai montré que la voie proBDNF/p75NTR module l'homéostasie chlore au cours du développement et dans des processus d’épileptogenèse. Pendant le développement, l’activation de la voie proBDNF/p75NTR contrôle le passage d’un GABA immature dépolarisant à un GABA mature hyperpolarisant via KCC2. Pendant l’épileptogenèse, le proBDNF via p75NTR contribuerait à l’hyperexcitabilité des réseaux neuronaux. De plus, le blocage de p75NTR permet de réduire le nombre de crises épileptiques. En conclusion, proBDNF/p75NTR est un facteur clé dans la séquence maturative du GABA et dans la mise en place de l’épilepsie du lobe temporalThe brain-derived neurotophic factor (BDNF) is synthesized as a precursor (proBDNF) that can be processed intracellularly to the mature form (mBDNF). mBDNF and proBDNF are assumed to produce opposing physiological responses mediated by the activation of two distinct classes of transmembrane receptors, the TrkB and the p75NTR respectively. The proteolysis of proBDNF is crucial for cognitive functions; its impairment may account for the emergence of brain disorders such as epilepsy. During my thesis, I showed that alteration in BDNF maturation in vitro triggers an up-regulation of p75NTR, inducing a disruption of GABAergic transmission. Moreover, in epilepsy, depolarizing and excitatory GABAergic responses, due to alteration of KCC2, have been reported. Interestingly, I described novel insights into the proBDNF/p75NTR mechanisms and function in vivo in modulating chloride homeostasis during the development of neuronal networks and in the pathogenesis of epilepsy. In physiological conditions, p75NTR activation by proBDNF may be a key regulator in shaping neural circuitry and synaptic plasticity. Moreover, I have shown that proBDNF/p75NTR to mBDNF/TrkB ratio may control the timing of the developmental shift of GABA depolarizing to hyperpolarizing. During epileptogenesis, proBDNF via p75NTR alters the excitatory/inhibitory equilibrium thereby enhancing neuronal activity through the inhibition of KCC2 function. Hence, blockade of p75NTR can prevent some of the epileptogenic mechanisms. Altogether, these data provide the first compelling evidence that proBDNF disrupts the GABA excitatory/inhibitory developmental sequence, which then favors the emergence of epileptic disorders
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Hünnerkopf, Regina. "Assoziationsstudien von Kandidatengenen (VMAT2, DAT, BDNF) mit Persönlichkeitsmerkmalen und psychiatrischen Erkrankungen." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976718324.
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Singh, Bhumika. "Differential regulation of glutamatergic and GABAergic synaptogenesis by BDNF and PRG1." [S.l.] : [s.n.], 2005. http://www.diss.fu-berlin.de/2005/339/index.html.
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Belsham, Ashley A. G. "The role of NMDA receptors and BDNF in learning and memory." Thesis, Nottingham Trent University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510175.
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Ramos, Catarina Esteves Lopes. "Wild-type huntingtin function in BDNF transcription and in neural differentiation." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7161.
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Fernandes, Brisa Simões. "Fator neurotrófico derivado do cérebro (BDNF) no transtorno bipolar : uma metanálise." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2009. http://hdl.handle.net/10183/18503.
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Objetivos: o Fator Neurotrófico Derivado do Cérebro (BDNF) desempenha um papel central na neurogênese e plasticidade sináptica. O Transtorno Bipolar (TB) é um dos mais graves transtornos psiquiátricos e está associado a maus resultados. Alguns estudos sugerem que o BDNF está diminuído durante os episódios de humor, e normal durante a eutimia, mas esses resultados ainda são controversos. O objetivo deste estudo foi realizar uma metanálise de todos os estudos que mediram os níveis periféricos de BDNF em adultos com TB. Métodos: foi realizada uma revisão sistemática utilizando banco de dados eletrônicos. Os critérios de inclusão foram estudos com dosagem de BDNF em plasma ou soro in vivo em pacientes adultos com TB. O tamanho de efeito (ES) das diferenças de BDNF entre pacientes com TB em diferentes estados de humor e controles foi calculado. Resultados: treze estudos com 1.113 participantes foram incluídos. O BDNF se encontra diminuído tanto na mania quanto na depressão quando comparados aos controles (ES -0,81, IC 95% -1,11 a -0,52, p<0,0001 e ES -0,97, IC 95% -1,79 a -0,51, p=0,02, respectivamente). Os níveis de BDNF não foram diferentes na eutimia quando comparados com os controles (ES -0,20, IC 95% -0,61 a 0,21, p=0,33). A análise de metarregressão na eutimia mostrou que a idade (p<0,0001) e a duração da doença (p=0,04) influenciaram a variação no ES. Houve também um aumento nos níveis de BDNF após o tratamento da mania aguda (ES -0,63, IC 95% -1,11 a -0,15, p=0,01). Conclusões: os níveis de BDNF estão consistentemente reduzidos durante os episódios maníacos e depressivos, e normalizam após o tratamento de mania aguda. Na eutimia, o BDNF diminui com a idade e o tempo de doença. Estes dados sugerem que o BDNF periférico possui potencial para se tornar um biomarcador de episódios de humor e de progressão de doença no TB.Objectives: Brain-derived neurotrophic factor (BDNF) plays a central role in synaptic plasticity and neurogenesis. Bipolar disorder (BD) is among the most disabling of all psychiatric disorders and is associated with poor outcomes. Some studies suggest that BDNF is decreased during mood states, and normal during euthymia, but others do not. The aim of this study was to perform a meta-analysis of all studies that measured peripheral BDNF levels in adults with BD. Methods: We conducted a systematic review using electronic database. Inclusion criteria were studies that measured BDNF in plasma or serum in vivo in adult patients with BD. Effect Sizes (ES) of the differences in BDNF between patients with BD in different mood states and controls were calculated. Results: Thirteen studies with 1113 participants were included. The BDNF was decreased both in mania and depression when compared to controls (ES -0.81, 95% CI -1.11 to -0.52, p<0.0001 and ES -0.97, 95% CI -1.79 to -0.51, p=0.02, respectively). The BDNF levels were not different in euthymia when compared with controls (ES -0.20, 95% CI -0.61 to 0.21, p=0.33). Meta-regression analyses in euthymia showed that age (p<0.0001) and length of illness (p=0.04) influenced the variation in ES. There was also an increase in BDNF levels following the treatment for acute mania (ES -0.63, 95% CI - 1.11 to -0.15, p=0.01). Conclusions: BDNF levels are consistently reduced during manic and depressive episodes, and recover after the treatment for acute mania. In euthymia, BDNF decreases with age and length of illness. These data suggest that peripheral BDNF has the potential to be a biomarker of mood states and disease progression for BD.
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Rodrigues, Fernanda Odrzywolek. "Avaliação dos níveis séricos de BDNF em pacientes pediátricos com neoplasia." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/56619.
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INTRODUÇÃO: O câncer infantil representa cerca de 0,5 a 3% de todas as neoplasias da população em geral. Do ponto de vista clínico, os tumores infantis crescem rapidamente e são mais invasivos que as neoplasias adultas, porém respondem melhor ao tratamento e são considerados de melhor prognóstico. As neurotrofinas e seus receptores (receptores de quinase relacionados à tropomiosina - Trk) são importantes reguladores da sobrevivência, desenvolvimento e plasticidade neuronal. Além disso, estão envolvidas no processo oncogênico, podendo facilitar ou suprimir o crescimento tumoral. O BDNF (brain-derived neurotrophic factor) é uma das neurotrofinas e possui ligação específica com o receptor TrkB, e também está envolvida em diferentes processos corporais. OBJETIVOS: Avaliar os níveis séricos de BDNF em pacientes pediátricos (crianças e adolescentes) com algum tipo de neoplasia e indivíduos sem doença, e avaliar a sua relação com sexo, idade, valor de plaquetas e sobrevida. MATERIAL E MÉTODOS: Estudo transversal com crianças e adolescentes com idade entre zero a 18 anos. Foram incluídos no estudo 114 pacientes, sendo 72 pacientes do grupo de crianças com neoplasia e 42 do grupo controle. A análise dos níveis séricos de BDNF foi realizada através da técnica de ELISA. O projeto foi aprovado pelo Comitê de Ética em Pesquisa do HCPA. RESULTADOS: As medianas (P 25-75) dos valores de BDNF foram 2,45 (0,76-5,23) pg/ml para o grupo com LLA, 0,45 (0,08-0,80) pg/ml para o grupo com LMA, 9,0 (3,14-14,7) pg/ml para o grupo com linfomas e tumores sólidos e 6,08 (2,60-9,35) pg/ml para o grupo controle. Não houve diferença entre os valores de BDNF quando comparados as varíaveis sexo e idade entre os diferentes grupos. Em relação aos valores de BDNF e plaquetas, houveram diferenças significativas entre os grupos de Leucemias e os demais grupos. Pacientes com neoplasia que tinham valores de BNDF menores que 4,00 pg/ml apresentaram uma menor sobrevida (p<0,05). CONCLUSÃO: Os resultados mostram diferenças significativas nos níveis de BDNF em pacientes com tumores infanto-juvenil, principalmente entre as diferentes neoplasias e até mesmo podendo ter influência na sobrevida destes pacientes. Porém mais estudos são necessários para investigar o papel das neurotrofinas nesta população, para quem sabe no futuro serem utilizadas como biomarcadores ou novos alvos terapêuticos.BACKGROUND: The childhood cancer represents about 0.5 to 3% of all cancers of the general population. From a clinical standpoint, infant tumors grow quickly and are more invasive than the adult cancers, but respond better to treatment and are considered a better prognosis. The neurotrophins and their receptors (tropomyosin-related kinase - Trk) are important regulators of survival, development and neuronal plasticity. They are also involved in the oncogenic process, which can facilitate or suppress tumor growth. BDNF (Brain-derived neurotrophic factor) is a neurotrophin that has a specific binding with the receptor TrkB, and is also involved in different bodily processes. This study aimed to evaluate the serum levels of BDNF in pediatric patients (children and adolescents) with some type of cancer and healthy individuals, as well its relationship with gender, age, platelet value and survival. PATIENTS AND METHODS: Cross-sectional study with children and adolescents aged zero to 18 years. The study included 114 patients, 72 patients in the group of children with cancer and 42 control group. Analysis of the serum levels of BDNF was performed by ELISA. The project was approved by the Ethics Committee of HCPA. RESULTS: The median (P 25-75) values of BDNF were 2,45 (0,76-5,23) pg/ml for the group with ALL, 0,45 (0,08-0,80) pg/ml for the group with LMA, 9,0 (3,14-14,7) pg/ml for the group with lymphomas and solid tumors and 6,08 (2,60-9,35) pg/ml in the control group. There was no difference between the values of BDNF compared the gender and age among the different groups. Regarding the values of BDNF and platelets, there were significant differences between groups of patients diagnosed with leukemias and other groups. Patients with cancer who had BDNF values lower than 4,00 pg/ml had a lower survival curve (p<0,05). CONCLUSION: The results show significant differences in BDNF levels in patients with tumors, especially among different tumors and even may have an influence on patient survival. But more studies are needed to investigate the role of neurotrophins in this population, who knows in the future be used as biomarkers or new therapeutic targets.
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Farias, Caroline Brunetto de. "BDNF/TrkB em câncer colorretal : interações funcionais com GRPR e EGFR." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/72306.
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BDNF/TrkB são descritos em diversas neoplasias onde iniciam sinais mitogênicos, facilitam o crescimento tumoral, previnem apoptose e regulam angiogênese e metástase. Outros fatores de crescimento também são importantes para tumorigênese, como GRP/GRPR e EGF/EGFR. O objetivo geral deste trabalho foi investigar o papel de BDNF/TrkB em câncer colorretal avaliando possíveis interações com GRPR e EGFR. Verificamos que BDNF e seu receptor, TrkB, estão presentes em amostras de pacientes com câncer colorretal esporádico, e os níveis de BDNF encontram-se mais elevados no tecido neoplásico que no tecido adjacente ao tumor. O tratamento com RC- 3095, um antagonista de GRPR, na linhagem celular de câncer colorretal humana, HT-29, causa diminuição nos níveis de NGF secretados pelas células e aumento de BDNF em relação ao controle não tratado. RC-3095 inibe a proliferação e viabilidade celular das linhagens HT-29 (EGFR positiva) e SW-620 (EGFR negativa), embora apenas em HT-29 ocorra um aumento significativo na expressão de mRNA de BDNF. Por isso, um anticorpo monoclonal anti-EGFR, cetuximabe, foi combinado a RC-3095, nas células HT-29, sendo capaz de prevenir tal aumento, sugerindo que este efeito seja mediado por EGFR. Os tratamentos com um inibidor de Trks, K252a (1000 nM) ou com cetuximabe (10 nM) também inibem a proliferação celular. Entretanto, a combinação de BDNF a cetuximabe previne este efeito, enquanto que a combinação de doses não efetivas de K252a (10 nM) à cetuximabe (1 nM) inibe a proliferação celular de HT- 29. Além disso, cetuximabe também causa aumento na expressão de mRNA de TrkB e BDNF, após 600 minutos de tratamento. Nossos resultados sugerem que a inibição da proliferação celular in vitro ou do crescimento tumoral in vivo devem acontecer através do bloqueio combinado entre GRPR e TrkB em células de câncer colorretal EGFR positivas, e que BDNF também esteja envolvido em mecanismos de resistência a fármacos. Por isso, o bloqueio de BDNF / TrkB pode emergir como potencial alvo antitumoral.BDNF / TrkB are described in various cancers where they participate in tumor growth, apoptosis, angiogenesis and metastasis. Furthermore, other growth factors are also important to tumorigenesis as GRP/GRPR and EGF/EGFR. Therefore, the aim of this study was to investigate the role of BDNF/TrkB in colorectal cancer evaluating the interactions with GRPR and EGFR. We found that BDNF and its receptor, TrkB, are present in samples from patients diagnosed with sporadic colorectal cancer, and BDNF levels were higher in tumor tissue compared to adjacent tumor tissue. Treatment with RC-3095, GRPR antagonist, in human colorectal cancer cell line, HT-29 caused a decrease in NGF levels secreted by cells, and generated increase of BDNF when compared to untreated control. RC-3095 inhibited the proliferation and cell viability in HT-29 (EGFR positive) and SW-620 (EGFR negative), but only HT-29 cells showed a significant increase in BDNF mRNA expression. Therefore, a monoclonal anti-EGFR antibody, cetuximab was combined with RC-3095 in HT-29 cells, and was able to prevent such an increase, suggesting that this effect is mediated by EGFR. The treatment with a Trk inhibitor, K252a (1000 nM) or cetuximab (10 nM), inhibited cell proliferation. However, the combination of BDNF with cetuximab prevented this effect, whereas the combination of ineffective doses of K252a (10 nM) with cetuximab (1 nM) still inhibited cell proliferation of HT-29. Furthermore, cetuximab also caused an increase in BDNF and TrkB mRNA expression, 600 minutes after treatment. In summary, our results suggest that inhibition of cell proliferation in vitro or tumor growth in vivo must occur between the combination of GRPR and TrkB in EGFR positive colorectal cancer cells, and that BDNF is also involved in drug resistance mechanisms. Therefore, blockage of BDNF / TrkB may emerge as potential antitumor target.
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Ramos, Catarina Esteves Lopes. "Wild-type huntingtin function in BDNF transcription and in neural differentiation." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7161.
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FALCICCHIA, Chiara. "BDNF delivery strategies in an experimental model of temporal lobe epilepsy." Doctoral thesis, Università degli studi di Ferrara, 2015. http://hdl.handle.net/11392/2388988.
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Neurotrophic factors (NTFs) have been reported to play opposite, pro- and/or anti-epileptic
effects in experimental models. Some NTFs favor epileptogenesis or progression of epilepsy
whereas others oppose these processes. Still other NTFs, including Brain-Derived
Neurotrophic Factor (BDNF), can exert both positive and negative effects. Moreover, BDNF
has been clearly shown to be involved in all the cellular and tissue changes that occur during
epileptogenesis. To get further insight in the involvement of BDNF in epilepsy and, on this
basis, to develop new therapeutic strategies, there is a need to develop new, advanced tools for
the modulation of the BDNF signal within defined brain regions. Therefore, the aim of this
thesis was to develop new delivery systems to block or to enhance the BDNF signal.
Specifically, the thesis deals the investigation of the validity of BDNF as a therapeutic target,
using advanced tools to down regulate BDNF expression (Herpes simplex virus-1 based
amplicon vectors) and to continuously secrete it [encapsulated cell biodelivery (ECB)
devices].
Two amplicon-based silencing strategies have been developed. The first, antisense (AS),
targets and degrades the cytoplasmic mRNA pool of BDNF, whereas the second, based on the
convergent transcription (CT) technology, directly represses the BDNF gene. In vitro (cell
lines) and in vivo (stereotaxic injection in the epileptic hippocampus) experiments
demonstrated a reliable effect of amplicon vectors in knocking down gene expression.
However, whereas the CT-BDNF strategy proved effective only in vitro, the AS-BDNF
amplicon vector proved effective both in vitro and in vivo, knocking down efficiently BDNF
protein levels in the injected hippocampus at different time points. The antisense strategy
seems therefore a better choice for silencing BDNF expression in vivo.
For a prolonged administration of BDNF, BDNF-producing cells encapsulated in ECB devices
have been tested in a rat model of Temporal Lobe Epilepsy. These devices, implanted
bilaterally in the hippocampus of chronically epileptic animals, proved capable to significantly
decrease the frequency of spontaneous generalized seizures.
These new tools and experiments help to further elucidate the role of BDNF in epilepsy and
provide an initial proof-of-concept for a new, promising therapeutic approach.
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Kemp, Christopher James. "Plasma Levels of Brain-Derived Neurotrophic Factor in Obese Women Randomly Assigned to a Very Low-Carbohydrate Diet Or an Energy-Restricted Low-Fat Diet." Cincinnati, Ohio : University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc//view?acc_num=ucin1175255390.
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Thesis (M.S.)--University of Cincinnati, 2007.Advisor: Dr. Kim N. Dietrich . Title from electronic thesis title page (viewed May 30, 2010). Includes abstract. Keywords: BDNF; Hypothalamus; Obesity; Weight loss. Includes bibliographical references.
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Banoujaafar, Hayat. "Contribution de l'hémodynamique cérébrale à l'élévation des taux de BNDF cérébraux induite par l'activité physique chez le rat." Thesis, Dijon, 2015. http://www.theses.fr/2015DIJOPE01/document.
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La pratique régulière d’une activité physique (AP) est un important message de santé publique. L’AP améliore non seulement la santé cardiovasculaire via l’augmentation de la production de NO (nitric oxide) par l’endothélium vasculaire mais aussi la santé cérébrale via l’augmentation des taux de BDNF (brain-derived neurotrophic factor) dans le cerveau. Comme la synthèse et la sécrétion de BDNF sont proportionnelles à l’activité neuronale, il est généralement admis que l’élévation des taux cérébraux de BDNF induite par l’AP est à relier à l’hyperactivité neuronale. Nous avons testé l’hypothèse selon laquelle l’élévation du flux sanguin dans les vaisseaux de la circulation cérébrale pendant la réalisation de l’AP contribue à augmenter les taux cérébraux de BDNF. Les expériences ont été menées chez des rats soumis ou non à l’AP (tapis roulant). Nos résultats montrent : 1) que l’augmentation des taux de BDNF induite par l’AP (tapis roulant, 18m/min, 30 min/j, 7j consécutifs) est moindre lorsque l’augmentation du flux sanguin pendant la réalisation de l’AP, est prévenue par un clampage mono- ou bi- carotidien, 2) que l’effet de l’AP sur les taux de BDNF dépend de l’intensité de l’AP ( tapis horizontal versus déclive descendant), 3) que la dysfonction endothéliale (modèle de rat spontanément hypertendu) et le traitement par un inhibiteur de NO synthase diminuent les effets de l’AP sur les taux cérébraux de BDNF et 4) qu’il existe une association positive entre les taux cérébraux de BDNF et la production de NO par l’endothélium vasculaire.L’ensemble de nos résultats suggère que l’augmentation des taux cérébraux de BDNF induite par l’AP met en jeu l’augmentation du flux sanguin dans les vaisseaux de la circulation cérébrale et, plus précisément, l’augmentation de la production endothéliale de NO qui en résulte. Ils fournissent de nouvelles données pour comprendre le lien existant entre fonction endothéliale et performances cognitives, soulevant l’idée selon laquelle les modalités d’AP pour améliorer la santé cérébrale doivent être différentes en cas de pathologies associées à une dysfonction endothélialeThe regular practice of physical activity (PA) is an important public health message. PA not only improves cardiovascular health through the increase in NO (nitric oxide) production by the vascular endothelium but also through the increase levels in brain BDNF (brain-derived neurotrophic factor) levels. As the synthesis and secretion of BDNF are proportional to neuronal activity, it is generally accepted that PA-induced brain BDNF levels elevation is linked to neuronal hyperactivity. We tested the hypothesis that the increase in blood flow in cerebrovasculature during PA contributes to increase brain BDNF levels. The experiments were carried out in sedentary and trained rats (treadmill). Our results show that: 1) brain BDNF levels elevation induced by PA (treadmill, 18m /min, 30 min /day, 7 consecutive days) is lower when the normal rise of cerebral blood flow during the PA is prevented by occluding one or both common carotid arteries, 2) the effect of PA on brain BDNF levels is dependent on PA intensity (horizontal versus downhill), 3) the presence of endothelial dysfunction (spontaneously hypertensive rat model) as well as NO synthase inhibition decrease the effects of PA on brain BDNF levels and 4) there is a positive association between brain BDNF levels and vascular endothelium NO production .Collectively, our results suggest that increase in brain BDNF levels, induced by PA, involves increase in cerebrovasculature blood flow and more precisely elevation in endothelium NO production. They provide new data for understanding the relationship between endothelial function and cognitive performance, raising the idea that PA modalities to improve brain health might be different in pathologies diseases with endothelial dysfunction
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Cefis, Marina. "Impact des modalités d'un exercice physique sur la neuroplasticité. Focus sur les sources de BDNF." Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCK049/document.
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L’exercice physique (EX) est reconnu comme la stratégie non pharmacologique la plus efficace pour améliorer la santé cérébrale. Les études menées chez l’Homme et l’animal s’accordent pour impliquer le brain-derived neurotrophic factor (BDNF), une neurotrophine dont les taux cérébraux augmentent en réponse à l’EX et qui est unanimement reconnue comme une molécule de signalisation cruciale de la neuroplasticité. Principalement exprimé par les neurones, le BDNF est également très exprimé par la cellule endothéliale et la cellule musculaire. Très largement sollicités lors d’un effort physique, l’endothélium et le muscle pourraient intervenir dans les effets positifs induits par l’EX. Bien qu’il existe aujourd’hui un consensus sur l’implication du BDNF dans les effets cérébraux de l’EX, il n’en existe pas concernant les modalités d’EX à pratiquer pour optimiser de manière efficace la plasticité cérébrale. Dans ce contexte, les objectifs de ces travaux étaient de déterminer l’impact des modalités de l’EX sur les expressions protéiques de BDNF dans différents territoires (cerveau, endothélium, muscle) et d’étudier les mécanismes à l’origine de l’augmentation de BDNF en réponse à l’EX.Nos résultats montrent que 1) l’expression du BDNF dans des vaisseaux périphériques de même territoire vasculaire (diamètre interne différent) est similaire en réponse à l’EX et majoritairement d’origine endothéliale, 2) l’augmentation de l’expression cérébrale de BDNF en réponse à l’EX dépend de l’intensité de l’EX, mais pas du type de contraction (excentrique/concentrique), 3) la mémoire est restaurée par un EX de forte intensité, 4) l’EX n’impacte pas l’expression musculaire de BDNF, mais augmente l’expression du précurseur de l’irisine (FNDC5), 5) l’expression du BDNF dépend de la composition du muscle en fibres musculaires, 6) les effets cérébraux de l’intensité de l’EX ne semblent pas être reliés à la surexpression de l’irisine musculaire.En conclusion, nos données démontrent que l’EX impacte positivement l’expression endothéliale, cérébrale mais pas musculaire de BDNF. Les résultats mettent en évidence l’importance du paramètre intensité de l’EX sur les taux cérébraux de BDNF. Enfin, selon nos données obtenues, l’irisine et le BDNF musculaires ne semblent pas être impliqués dans l’augmentation cérébrale de BDNF en fonction de l’intensité de l’EXPhysical exercise (EX) is recognized as the most potent non-pharmacological strategy to positively enhance brain health. From Human and animal studies there is a consensus to involve brain-derived neurotrophic factor (BDNF), a neurotrophin strongly expressed in response to EX and implicated in neuroplasticity mechanisms. Mainly expressed by neurons, BDNF is also expressed by endothelial and muscle cells. Largely sought during a physical effort, endothelium and skeletal muscle could be involved in positive effects induced by EX. Although there is a real consensus about BDNF and cerebral effect of EX, the typology of the better regimen of EX to enhance cerebral plasticity is not known. In this context, objectives of this works were to determine the impact of EX modalities on BDNF protein expression in different territory (brain, endothelium and muscle) and to identify mechanisms related in BDNF increases in response to EX.Our results showed that 1) BDNF expression in peripheral vessels from the same vascular territory (distinct internal diameter) is similar in response to EX, 2) cerebral BDNF increases induced by EX is dependent on EX intensity but not on the type of contraction (eccentric/concentric), 3) memory is restored by high intensity EX, 4) after EX, BDNF muscular expression is unchanged while the precursor of irisine (FNDC5) expression is increased, 5) BDNF expression depends on muscular fibers typology, 6) cerebral beneficial effects of EX intensity is might not be related to muscular irisine production.In conclusion, our data demonstrated that EX positively impact endothelial, cerebral but not muscular BDNF expression. Results highlighted the importance of the intensity parameter of EX on cerebral BDNF levels. Finally, according to our data, irisine and BDNF from the muscle might not be related to the cerebral increases of BDNF induced by EX intensity
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Junior, José Ribeiro Lemos. "Influência da variante Val66Met na expressão do gene brain-derived neurotrophic factor (BDNF) em resposta ao treinamento físico aeróbio." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-24022016-160932/.
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O fator neurotrófico derivado do cérebro (BDNF) tem sido associado com a angiogênese por meio do seu receptor específico tropomiosina quinase B (TrkB). Uma vez que ambos são expressos em células endoteliais vasculares e o treinamento físico aeróbio (TF) pode aumentar os níveis séricos de BDNF, este estudo teve como objetivo testar as hipóteses de que: 1) Os níveis séricos de BDNF modulam o fluxo de sangue periférico; e 2) A presença do alelo Met no polimorfismo BDNF Val66Met prejudica o ganho de vasodilatação por TF. Foram genotipados para o polimorfismo do gene BDNF 304 voluntários saudáveis do sexo masculino (Val66Val, n = 221; Val66Met, n = 83) que foram submetidos a intenso TF em uma pista de corrida 3 vezes/semana durante 4 meses. Foram avaliados pré e pós-TF as concentrações circulantes de BDNF e pró-BDNF (ELISA), frequência cardíaca (FC), pressão arterial média (PAM), o fluxo de sangue do antebraço (FSA) e resistência vascular periférica (RVP). No período pré-TF, BDNF, pró-BDNF, a razão BDNF/pró-BDNF, FSA e RVP foram semelhantes entre todos os genótipos. Depois do TF, a capacidade funcional (VO2pico) aumentou e houve a diminuição da FC de repouso de forma semelhante em ambos os grupos. O grupo Val66Val, mas não o Val66Met, aumentou os níveis de BDNF (interação, p=0,04) e aumentou a razão BDNF/pró-BDNF (interação, p < 0,001). Curiosamente, as respostas do FSA (Interação, p=0,04) e da RVP (Interação, p=0,01), durante o exercício handgrip, do grupo Val66Val, apresentou melhoras quando comparado com o grupo Val66Met, mesmo com respostas similares de FC e PAM. Outras análises mostraram associação entre a razão BDNF/pró-BDNF e FSA (R=0,64; p < 0,001) e RVP (R=-0,58; p < 0,001). Estes resultados mostram que, em resposta ao TF, tanto a reatividade vascular periférica quanto o BDNF circulante são prejudicados pela presença do polimorfismo Val66Met do gene BDNF e esta responsividade está associada às concentrações de BDNF sérico em indivíduos saudáveisThe neurotrophin Brain-derived neurotrophic factor (BDNF) has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Since both are expressed in vascular endothelial cells and aerobic training (ET) can increase serum BDNF levels, this study aimed to test the hypotheses that: 1) Serum BDNF levels modulate peripheral blood flow; and 2) The presence of the allele Met in the BDNF Val66Met polymorphism impairs vasodilation gain by ET. We genotyped for BDNF polymorphism 304 healthy male volunteers (Val66Val, n= 221; Val66Met, n=83) which underwent to intense aerobic ET on a running track 3 times/week for 4 months. We evaluated pre and post ET serum BDNF and proBDNF concentration (ELISA), heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF) and forearm vascular resistance (FVR). In the pre ET, BDNF, proBDNF, BDNF/proBDNF ratio, FBF and FVR were similar between all genotypes. After ET, functional capacity (VO2peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (Interaction, p= 0.04) and BDNF/proBDNF ratio (Interaction, p < 0.001). Interestingly, FBF (Interaction, p=0.04) and the FVR (Interaction, p=0.01) responses during handgrip exercise improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. Further analyses showed association between BDNF/proBDNF ratio and FBF (R=0.64, p < 0.001) and FVR (R=-0.56, p < 0001). These results show that peripheral vascular reactivity and serum BDNF responses to ET are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated to the serum BDNF concentrations in healthy subjects
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Bem, Tiago Henrique Camara De. "Efeito da pré-maturação sobre o desenvolvimento embrionário de oócitos submetidos à ativação partenogenética e transferência de núcleo." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/74/74131/tde-08092009-114443/.
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As taxas de produção embrionária tanto da FIV (30-40%) como da TN (23%) ainda estão aquém do esperado. Desta forma, a pré-maturação com inibidores do ciclo celular é uma das alternativas que vem sendo estudada para aumentar a competência dos oócitos utilizados na PIV, na tentativa de otimizar o sucesso das biotécnicas. Sabe-se que neurotrofinas desempenham funções no sistema reprodutor. O BDNF é um exemplo de neurotrofina que parece estar relacionada com a maturação dos oócitos. Desta forma, o objetivo deste trabalho foi de aperfeiçoar a pré-maturação e a maturação in vitro de oócitos bovinos submetidos posteriormente à ativação partenogenética, visando seu uso na biotécnica de transferência de núcleo. Oócitos bovinos foram submetidos à maturação na presença (MIV/BD) ou ausência (MIV) de BDNF ou pré-maturados com BLI e suplementados (BL/BD) ou não (BL) com a neurotrofina. Posteriormente foram avaliados quanto à taxa de maturação (metáfase II), ativação (formação de prónúcleo) e desenvolvimento embrionário (produção e qualidade dos blastocistos). Não houve diferença (P>0,05) entre taxas de MII após a maturação com ou sem BDNF. Porém, o grupo pré-maturado e suplementado (BL/BD n=73; 91,2%) apresentou maior taxa de MII (P<0,05) em relação ao grupo não suplementado (BL n=66; 76,7%). Oócitos maturados nas mesmas condições foram ativados quimicamente para análise do desenvolvimento embrionário. Os grupos MIV/BD (n=30; 71,4%) e MIV (n=41; 91.1%) apresentaram diferença (P<0,05) em relação à taxa de ativação. Porém, não foi observada diferença quanto aos outros parâmetros do desenvolvimento. Quando os oócitos foram pré-maturados a taxa de clivagem do grupo suplementado (BL/BD: n=227; 65,2%) foi superior (P<0,05) ao grupo não suplementado (BL: n=187; 57,7%), mas não foram observadas diferenças (P>0,05) para os outros parâmetros de desenvolvimento. A qualidade dos embriões ativados também não foi afetada pelos tratamentos. Os grupos submetidos à TN (MIV e BL/BD) apresentaram diferenças (P<0,05) para extrusão do 1°CP (n=639; 63,5% e n=693; 69,5%, respectivamente) e para taxa de fusão (n=345; 72,9% e n=397; 79,2%, respectivamente) não havendo diferença para nenhum outro parâmetro avaliado. A qualidade dos embriões clonados também foi avaliada e não foi observada diferença. Após a transferência dos embriões dos grupos MIV (n=28) e BL/BD (n=26) para as receptoras, os grupos foram capazes de produzir gestação avançadas (10,7 e 11,5%, respectivamente) de forma similar (P>0,05). Com base nestes resultados podemos concluir que a suplementação, tanto da maturação como a pré-maturação não causa prejuízo no posterior desenvolvimento embrionário. Ainda, embriões clonados produzidos a partir de oócitos bloqueados são capazes de estabelecer gestações avançadas em bovinos.Embryo production rates obtained from both IVF (30-40%) and NT (23%) are still below the expected values. Therefore, oocyte pre-maturation using cell cycle inhibitors is one of the alternatives which has been studied to increase the competence of oocytes used for IVP, as an attempt to optimize the success rates of these biotechniques. Neurotrophins are known to play several roles in the reproductive system. BDNF is an example of a neurotrophin that seems to be related to oocyte maturation. Therefore, the objective of this study was to improve techniques of pre-maturation and maturation of bovine oocytes submitted to parthenogenetic activation, aiming for its use on cloning by nuclear transfer. Bovine oocytes were submitted to maturation either in presence (IVM/BD) or absence (IVM) of BDNF or pre-matured with BLI and supplemented (BL/BD) or not (BL) with the neurotrophin. Groups were evaluated for maturation rates (metaphase II), activation (pro-nucleus formation) and embryo development (blastocyst formation rate and quality). There was no difference (P>0.05) in MII rate after the maturation with or without BDNF. However, pre-maturation in the supplemented group (BL/BD, n=73; 91.2%) resulted in higher MII rate (P<0.05) when compared with the nonsupplemented group (BL, n=66; 76.7%). Oocytes which were matured under the same conditions were also activated chemically for embryonic development analysis. Activation rates were different (P<0.05) from IVM/BD groups (n=30; 71.4%) and IVM (n=41; 91.1%). However, no difference were observed for development parameters. When the oocytes were prematured, cleavage rates in the supplemented group were superior (P<0.05) than non supplemented group (BL/BD: n=227; 65.2%) and (BL: n=187; 57.7%), but no difference was observed for other developmental parameters. Embryo quality was also evaluated and no difference was observed between treatments. Groups submitted to NT (IVM and BL/BD) differed regarding (P<0.05) the 1stPB extrusion (n=639; 63.5% and n=693; 69.5%, respectively) and fusion rate (n=345; 72.9% and n=397; 79.2%, respectively), but did not present differences for other evaluated parameters. Embryo quality was evaluated again and no differences were observed. After the embryos were transferred to recipient cows, groups IVM (n=3; 10.7%) and BL/BD (n=3; 11.5%) were capable of producing advanced gestations at similar rates (P>0.05). Based on these results, it may be concluded that supplementation of both maturation and pre-maturation does not impair embryonic development. Additionally, cloned embryos produced from blocked oocytes are able to establish advanced gestation in cattle.
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Ibarguen, Vargas Nylza Yadira. "Implication du BDNF dans l'étiopathogenèse et le traitement des troubles anxio-dépressifs : aspects précliniques." Thesis, Tours, 2008. http://www.theses.fr/2008TOUR4004/document.
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Bien que les troubles anxio-dépressifs représentent une des principales causes d’invalidité et un des plus sérieux problèmes de santé dans le monde, les mécanismes neurobiologiques à l’origine de ces affections demeurent méconnus. Les processus mis en jeu semblent multiples et complexes : passant par des déséquilibres au niveau des neurotransmetteurs jusqu’à des modifications de la plasticité neurale et du remodelage cellulaire. Les neurotrophines étant considérées comme les principaux régulateurs de la plasticité, l’hypothèse d’un lien causal entre le niveau de neurotrophine, principalement de l’une d’entre elles, le Brain-Derived Neurotrophic Factor (BDNF) et l’apparition de troubles anxio-dépressifs a ainsi été proposée. Notre travail a donc eu pour objectif l’étude de l’implication du BDNF dans l’étiopathogenèse et le traitement des troubles anxio- dépressifs à travers l’utilisation de modèles murins. Etant donné que plusieurs études cliniques et précliniques ont montré une implication du BDNF dans plusieurs traits psychologiques et comportementaux, nous avons cherché à déterminer si des différences dans le gène BDNF pouvaient être à l’origine de la grande hétérogénéité comportementale des différentes souches de souris. Nous rapportons dans cette étude l’existence d’un polymorphisme sur un seul nucléotide (SNP) à l’origine d’un changement d’acide aminé (une leucine est remplacé par une méthionine) en position 32 dans la séquence du prodomaine du BDNF. Nous démontrons ensuite que, bien que ce SNP ne modifie par l’expression basale de BDNF dans le cerveau, ce polymorphisme est associé au phénotype « anxieux » des souris. Par contre, il n’est pas impliqué dans le comportement alimentaire, le toilettage, l’activité, l’apprentissage et la mémoireAlthough anxio-depressive disorders are a major cause of disability with important health consequences, the underlying neurobiological mechanisms remain largely unknown. Neurotransmitter imbalances can change numerous intracellular signaling pathways that ultimately result in lasting modifications in neural plasticity and cellular remodeling. Since neurotrophins, and particularly brain-derived neurotrophic factor (BDNF), are considered main regulators of neural plasticity, changes in the expression of these genes are an attractive mechanism by which normally differentiated brain cells may transform into a pathological anxio-depressive phenotype. A first study seven strains of mice with large behavioral differences were used to investigate whether differences in the expression and sequence BNDF may be associated with anxiety and depressive traits. A change of a single nucleotide in position 32 of prodomain sequence of BNDF, which resulted in a leucine being replaced by methionine, was associated with mice exhibiting the anxious phenotype. Mice carrying the Met allele had greater propensity to neophobic reactions and behaviors related to anxiety. However, this polymorphism did not alter the basal expression of the gene and other behavioral activities including appetite, thirst, grooming, learning and memory. Furthemore, when chronic stress slightly unpredictable (UCMS) was used in seven mouse lines, no association was observed between Leu 32 Met and depression-like effectors due to antidepressant treatments. When heterozygous (+/-) BNDF mice were used in the UCMS model, no changes were noted in physical observations (i.e, hair coat, weight), behavioral responses (to mimic anxiety, aggressiveness and resignation) and in the stress hormones; by contrast, some effects to the anti-depressants were different from the ones seen in homozygous (+/+) mice. In conclusion, BDNF polymorphisms can contribute to the various behavioral profiles exhibited by different strains of mice in test of anxiety. However, it does not appear to be involved in the etiopathogenesis of depression
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Geoffroy, Hélène. "Mécanismes moléculaires et cellulaires de la « mémoire neurochimique » induite par la morphine et perspectives thérapeutiques." Electronic Thesis or Diss., Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB168.
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L'addiction est une maladie psychiatrique aux conséquences lourdes dans nos sociétés modernes tant d'un point de vue économique que de santé publique. Lors du sevrage après un traitement chronique, des adaptations à long terme se mettent en place au niveau neurochimique et morphologique. Les épisodes de rechutes subsistent, même après de longues périodes d'abstinence. Le but de ce travail de thèse a été de caractériser des adaptations qui se mettent en place à court et long terme dans le noyau accumbens (Nac) lors du sevrage après un traitement chronique à la morphine (10 mg/kg, s.c., 1 fois par jour pendant 14 jours). Nous nous sommes intéressés en particulier aux altérations ayant lieu spécifiquement à l’heure où les animaux avaient l’habitude de recevoir l’injection de morphine, par rapport à une autre heure de la journée. Nous avons mis en évidence une augmentation spontanée de dopamine extracellulaire dans le Nac au 1er et au 14ème jour d’arrêt du traitement, spécifiquement au moment où les rats recevaient l’injection de morphine, par rapport à une autre heure dans la journée. Il pourrait s’agir d’une anticipation du caractère renforçant positif de la drogue, conditionnée par l’heure de la prise de morphine. Des modifications dans la morphologie des neurones ont également été observées dont notamment une diminution de la densité des épines dendritiques spécifiquement dans les neurones épineux moyens du core du Nac à l’heure habituelle d’injection de morphine au 1er jour de sevrage. Ceci est en parti dépendant du stress induit par les injections car une augmentation de la densité des épines est observée lorsqu’une adrénalectomie est réalisée avant le début des traitements à la morphine. Parallèlement, nous nous sommes intéressés à la signalisation d’une neurotrophine impliquée dans les phénomènes de mémoire et d’apprentissage, le BDNF (Brain-Derived Neurotrophic Factor). Quatorze jours après l’arrêt des traitements, la signalisation du BDNF (les protéines de BDNF mature, le proBDNF, l’isoforme tronquée du récepteur TrkB.T1) augmente spontanément à l’heure habituelle d’injection de morphine par rapport à une autre heure de la journée, dans le core du Nac. L’augmentation de BDNF est retrouvée au niveau périphérique, au 1er et au 14ème jour de sevrage à l’heure habituelle d’injection de morphine, par rapport à une autre heure de la journée. Au niveau périphérique, nous avons montré que les variations de BDNF étaient spécifiques de la cocaïne et de la morphine et que le phénomène ne se généralise pas à une récompense naturelle. L’ensemble de ces résultats attire l’attention sur l’importance des modifications spontanées qui se mettent en place au cours du sevrage à l’heure habituelle d’injection de drogue et qui perdurent dans le temps. L’heure habituelle de consommation de la drogue constitue peut être une fenêtre de temps où les individus abstinents seraient plus vulnérables à la rechute, ceci pouvant être quantifiable objectivement via des mesures régulières du taux de BDNF périphériqueAddiction is a psychiatric disease with far-reaching consequences in our western countries both in economical and public health issues. Chemical and morphological alterations are observed in the brain during withdrawal following a chronic drug of abuse treatment. Even after a protracted abstinence, relapse to drug-seeking and drug-taking occurs. The aim of this research was to characterize the short and long term-alterations that took place in the nucleus accumbens (Nac) during withdrawal following a chronic morphine treatment (10 mg/kg, s.c., once a day during 14 days) We particularly focused our attention on the alterations that occurred specifically at the usual hour of morphine injection, compared to another hour of the day. We have stressed an increase of spontaneous extracellular dopamine in Nac on the 1st (WD1 for withdrawal day 1) and the 14th day (WD14 for withdrawal day 14) after the end of the treatment, especially at the time where rats were used to receive morphine, compared to another time of the day. This may reflect a neurochemical anticipatory response to the rewarding effects of morphine, which is a time-dependent conditioned response that mimic the effect of the drug, only at the usual hour of injection. Morphological alterations of accumbal neurons were also observed. On the 1st day of withdrawal, we reported a decrease of dendritic spine density of medium spiny neurons in the Nac core at the usual hour of injection compared to a basal level, measured at another time of the day. This is partly due to the stress induced by injections as an increase of dendritic spine density was reported when adrenalectomy was performed before the beginning of morphine treatment. In parallel, we also focus on the signaling pathway of a particular neurotrophin involved in learning and memory, called BDNF (Brain-Derived Neurotrophic Factor). Fourteen days after the end of the treatment, the BDNF signaling pathway (mature BDNF proBDNF and the truncated isoform the TrkB receptor proteins) increase at the usual hour of morphine injection compared to another hour of the day in the Nac core. We also found an increase in peripheral BDNF level, on WD1 and WD14 at the usual time of injection compared to another time of the day. We demonstrated that those peripheral BDNF alterations were specific of drugs of abuse (cocaine and morphine) as no alterations were reported with a natural reward (a butter biscuit). Taken together, these results shed light into the importance of the long- term alterations that take place during withdrawal at the usual time of drug injection. The hour at which an individual consumes drugs of abuse may constitute a time-window where abstinent patients may be more prone to relapse. This phenomenon may be objectively quantified by regular monitoring of peripheral BDNF level
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Moy, Jamie K., Arkady Khoutorsky, Marina N. Asiedu, Gregory Dussor, and Theodore J. Price. "eIF4E Phosphorylation Influences Bdnf mRNA Translation in Mouse Dorsal Root Ganglion Neurons." FRONTIERS MEDIA SA, 2018. http://hdl.handle.net/10150/627082.
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Plasticity in dorsal root ganglion (DRG) neurons that promotes pain requires activity-dependent mRNA translation. Protein synthesis inhibitors block the ability of many pain-promoting molecules to enhance excitability in DRG neurons and attenuate behavioral signs of pain plasticity. In line with this, we have recently shown that phosphorylation of the 5' cap-binding protein, eIF4E, plays a pivotal role in plasticity of DRG nociceptors in models of hyperalgesic priming. However, mRNA targets of eIF4E phosphorylation have not been elucidated in the DRG. Brain-derived neurotrophic factor (BDNF) signaling from nociceptors in the DRG to spinal dorsal horn neurons is an important mediator of hyperalgesic priming. Regulatory mechanisms that promote pain plasticity via controlling BDNF expression that is involved in promoting pain plasticity have not been identified. We show that phosphorylation of eIF4E is paramount for Bdnf mRNA translation in the DRG. Bdnf mRNA translation is reduced in mice lacking eIF4E phosphorylation (eIF4E(S209A)) and pro-nociceptive factors fail to increase BDNF protein levels in the DRGs of these mice despite robust upregulation of Bdnf-201 mRNA levels. Importantly, bypassing the DRG by giving intrathecal injection of BDNF in eIF4E(S209A) mice creates a strong hyperalgesic priming response that is normally absent or reduced in these mice. We conclude that eIF4E phosphorylation-mediated translational control of BDNF expression is a key mechanism for nociceptor plasticity leading to hyperalgesic priming.
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Jonsson, Josefine. "Effect of voluntary exercise on BDNF/TrkB gene expression and alcohol intake." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-86749.
Full textAbstract:
Voluntary wheel running is rewarding and believed to activate the same brain reward system as in alcohol and drug addiction. Brain-derived neurotrophic factor (BDNF), a well-known growth factor widely expressed in the brain, is modulated by both voluntary exercise and alcohol consumption. The aim of this study was to evaluate how voluntary exercise affects the expression levels of BDNF and its receptor TrkB in brain regions involved in positive and negative reinforcement. Additionally we wanted to evaluate the effect it may have on alcohol drinking behaviors in C57BL/6 mice, a mouse model which are naturally prone for engaging in voluntary exercise and voluntary alcohol consumption. We found a small upregulation in DG and CA1 after three weeks of exercise, confirming findings by others, and a significant 3-fold downregulation of BDNF in NAc after both three weeks of exercise and exercise followed by a five week period of either ethanol intake or not. Interestingly, we here show a significant 100-fold increase in BDNF after exercise and a 120-fold increase after both exercise and alcohol consumption in amygdala, a region involved in regulation of anxiety-related behavior and negative reinforcement. Additionally a slightly lower 10-fold increase in BDNF was seen after exercise and a 15-fold increase after exercise followed by ethanol in prefrontal cortex, a structure contributing to reward-related behavior. Behaviorally, we could not either directly following exercise or at five weeks post-exercise detect any significant effect of wheel-running on depression-related behavior. However, we did find that exercise significantly increased the alcohol intake.