Dissertations / Theses on the topic 'Neurotrophins'
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1
Karchewski, Laurie Ann. "Neurotrophins and neurotrophin receptors in adult primary sensory neurons." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0034/NQ63884.pdf.
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Ward, Nicole L. "Neurotrophins and neurotrophin signal transduction in cholinergic neurons of the mouse forebrain." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0020/NQ49297.pdf.
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Timm, David Eugene. "Conformation, stability and interactions of the neurotrophins and the low-affinity neurotrophin receptor." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1057179020.
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Coppell, Alexander. "Antidepressant interactions with neurotrophins." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400564.
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Travaglia, Alessio. "Memory, metals and neurotrophins." Doctoral thesis, Università di Catania, 2013. http://hdl.handle.net/10761/1346.
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In the last decades, one of the main interests of neuroscientists has been to unravel the molecular mechanisms of memory.
Neurotrophins are proteins involved in development and survival of neurons as well as they are active player in memory formation and synaptic plasticity. d-block biometals, especially copper and zinc, are emerging as crucial player in the physiology of the brain.
As matter of fact, there is a significant overlap between brain areas in which the highest concentration of metals have been measured and those where the neurotrophins exert their biological activity. Metal ions can directly modulate their activities, through conformational changes, and/or indirectly by activating their downstream signaling in a neurotrophin-independent mode. Despite the importance of these modulations, there is the lack of experimental data regarding the coordination features of metal ions complexes with neurotrophins.
The N-terminal domain of neurotrophins is critical for the binding selectivity and activation of their receptors. We synthesized the N-terminus peptide fragments encompassing the human neurotrophins, characterized their copper(II) and zinc(II) complexes by means of potentiometric, spectroscopic (UV/Vis, CD, NMR and EPR) techniques and DFT calculations, tested the metal-driven biological effect. The coordination features of acetylated as well as single point mutated peptides have been also studied to prove the involvement of each donor group. The functional interaction of biometals with neurotrophins and related peptides has been tested by biological assay on SHSY5Y neuroblastoma cell, providing evidence of the correlation between biological activity and coordination environment.
Our biochemical characterizations of the neurotrophins signaling, both in vitro and in vivo, have shed some light on the possible use of neurotrophins and neurotrophins-like peptides in neurological disorders. Indeed, the use of neurotrophins in the early stages of neurodegenerative diseases has recently gained attention. However, there are limits to such therapy, e.g. insufficient permeability of the blood-brain barrier and inappropriate activation of receptors that trigger side effects. The use of peptidomimetic combined with
systems that guarantee their delivery might allow to overcome these restrictions. In view of application as functional nanoplatforms for smart drug delivery, supported lipid bilayers formed by neurotrophin peptidomimetics/small unilamellar vescicles adsorption on silica (both planar model and nanoparticles) have been characterized.
In conclusion, the interaction of metals and neurotrophins might represent a crossroad for neuronal physiology. Better understanding of metal ion-driven neurotrophins signal transduction and intercellular signaling, as well as vice versa, the role of neurotrophins in the control of metal ions homeostasis, could disclose helpful information and it is therefore strongly raising as one of the most critical step in the study of neurodegenerative diseases as well in the physiological mechanisms of memory.
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Marco, Salazar Paola. "The role of neurotrophins and neurotrophin receptors in the pathogenesis of neurodegeneration and neuroregeneration." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/285547.
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Las neurotrofinas son una familia de factores de crecimiento polipeptídicos estructuralmente relacionados que influyen en el desarrollo, mantenimiento, supervivencia, reparación y muerte de las células neuronales y no neuronales en el sistema nervioso.
Los miembros pertenecientes a este grupo que incluyen NGF, BDNF, NT-3 y NT 4/5, ejercen sus funciones intracelulares mediante la unión a dos tipos de receptores transmembrana muy diferentes; los receptores de tirosin quinasa (Trk A, B y C) y el receptor de neurotrofina p75 (p75NTR), un miembro perteneciente a la superfamilia del factor de necrosis tumoral (TNF).
Las neurotrofinas son objeto de estudio de la investigación actual debido a su participación tanto en condiciones fisiológicas como patológicas. Estudios previos publicados señalan las neurotrofinas como agentes terapéuticos prometedores.
En esta tesis, se llevó a cabo un estudio inmunohistoquímico de todas estas neurotrofinas (a excepción de NT4 / 5) y sus receptores en el sistema nervioso de diferentes modelos transgénicos murinos en dos escenarios diferentes: neurodegeneración del sistema nervioso central y neuroregeneración en el sistema nervioso periférico.
Con el fin de dilucidar los mecanismos neurodegenerativos asociados a la patogénesis de las enfermedades priónicas, un modelo murino (BoTg 110) de la encefalopatía espongiforme bovina (EEB), que sobreexpresa la proteína priónica celular bovina, fué sometido a una inoculación intracerebral con un inóculo de EEB. Se evaluaron los cambios neuropatológicos en el encéfalo y se compararon con el marcaje inmunohistoquímico de las NTs/NTRs. Además, en este experimento, se incluyó un modelo “wild type” (Balb-C) como control para realizar un completo mapeo del inmunomarcaje de las NTs/NTRs en el encéfalo –normal- de ratón. Se observó una correlación entre el incremento en el marcaje inmunohistoquímico del receptor p75, especialmente en células gliales con la distribución de lesiones asociadas a la EEB. Esto podría sugerir que, entre todos los factores neurotróficos evaluados, este receptor podría está implicado en la fase terminal de la patología de la EEB.
Además, el estudio del sistema nervioso periférico se llevó a cabo tras inducir experimentalmente un daño mecánico (aplastamiento o “crush”) en el nervio ciático en ratones transgénicos macho RIP-I / hIFNβ. En este modelo, el papel de las NTs/NTRs en los procesos de neuroregeneración se evaluó en el nervio, en los correspondientes ganglios de la raíz dorsal y en médula espinal a diferentes tiempos después de la cirugía. Se observaron cambios en la inmunorreactividad de todos los factores estudiados en estas tres estructuras. Observamos algunas particularidades en función del tiempo y la neurotrofina o receptor estudiado que se correspondían con la regeneración nerviosa.
Nuestros resultados indicaron que, las neurotrofinas, en particular el receptor p75, podrían ser estudiadas como posibles dianas terapéuticas para el tratamiento de las enfermedades priónicas. Del mismo modo, una combinación de neurotrofinas podría ser de utilidad para tratar pacientes afectados por lesiones de nervios periféricos, ayudando así al proceso regenerativo.
Profundizar en el conocimiento del papel que juegan las neurotrofinas en este contexto es indispensable para poder desarrollar tratamientos más eficaces de aquellos trastornos que afectan el sistema nervioso.Neurotrophins (NTs) are a unique family of structurally related polypeptide growth factors that influence the development, maintenance, survival, repair and death of neuronal and non neuronal cells in the nervous system. Members belonging to this group include NGF, BDNF, NT-3 and NT 4/5. They exert their intracellular roles by binding to two different transmembrane types of receptors; the tyrosine kinase receptors (Trk A, B and C) and the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor (TNF) superfamily. Neurotrophins are under current investigation for their involvement in physiological and pathological conditions. Previously published literature points them out as promising therapeutic agents. In this thesis, an immunohistochemical assessment of all these neurotrophins (with the exception of NT4/5) and their receptors was performed in the nervous system of different adult transgenic murine models in two different scenarios: central nervous system neurodegeneration and peripheral nervous system neuroregeneration. In order to determine the role of NTs/NTRs in the neurodegenerative mechanisms associated to prion diseases pathogenesis, the BoTg 110, a murine model of bovine spongiform encephalopathy (BSE), which overexpresses the bovine prion cellular protein, was subjected to an intracerebral inoculation with a BSE isolate. Neuropathological features where assessed and compared to NTs/NTRs immunolabelling. Furthermore, in this experiment, a wild type mouse line (Balb-C) was included as a control for a thorough -normal- mouse brain mapping of the NTs/NTRs immunolabelling. An increased expression of p75NTR, particularly in glial cells, was observed to correlate well with TSE related lessions. This may suggest that, among all neurotrophic factors evaluated, this receptor is involved in end stage brain pathology in BSE. Additionally, the study of the peripheral nervous system neuroregeneration was carried out following an experimental unilateral mechanic injury (crush) in the sciatic nerve of male transgenic RIP-I/hIFNβ mice. In this model, the involvement of NTs/NTRs in the neuroregenerative process was evaluated in the nerve, in the corresponding dorsal root ganglia and in the lumbar spinal cord segments at different time points after surgery. Our findings indicated changes in the immunoreactivity for all factors studied in these three structures. Particularities depending on the time point and studied NTs were observed related to the neuroregenerative processes Our results indicate that neurotrophins, and particularly the p75NTR could be further studied as possible therapeutic targets for prion diseases. Likewise, combined neurotrophins could be useful to treat patients affected by peripheral nerve injuries and therefore contributing to the peripheral nerve regeneration.A better understand ing of the mechanisms underlying the neutrophin function involvement is a prerequisite for the development of more effective treatments for the disorders affecting the nervous system
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Lichtenecker, Petra [Verfasser]. "Modulation der Sekretion des Neurotrophins "Brain-Derived Neurotrophic Factor" durch zyklisches Adenosinmonophosphat / Petra Lichtenecker." Magdeburg : Universitätsbibliothek, 2016. http://d-nb.info/1128726483/34.
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Agerman, Karin. "Specificity of neurotrophins in the nervous system : a genetic approach to determine receptor engagement by neurotrophins /." Stockholm, 2003. http://diss.kib.ki.se/2004/91-7349-730-4/.
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Watson, Judy J. "Neurotrophins and their receptors as therapeutics." Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431610.
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Mazouffre, Clément. "Rôles du couple TrkB/BDNF et de l’autophagie dans la survie de cellules de cancer colorectal." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0091/document.
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Le cancer colorectal (CCR) est le premier cancer digestif dans les pays occidentaux. Malgré les progrès thérapeutiques réalisés au cours des deux dernières décennies, la survie relative à 5 ans ne dépasse pas 56%, et s’abaisse à 11,3% pour les patients métastatiques. Le pronostic est lié au stade de développement de la maladie au moment du diagnostic. Les décès sont en rapport avec une résistance primaire de la masse tumorale aux thérapies, ou la survenue de récidive, en rapport avec une maladie microscopique résiduelle, non contrôlée par les thérapies systémiques adjuvantes. Le travail réalisé au sein de notre laboratoire portant sur deux voies de signalisation met en leurs rôles dans le CCR : les neurotrophines (NTs, facteurs de croissance impliqués dans la survie des cellules cancéreuses) et l’autophagie (processus de recyclage cellulaire impliqué dans la résistance au stress). Le but de cette étude a été d’analyser la part de ces deux voies dans la survie des cellules du cancer colo-rectal et l’impact de leur inhibition sur le devenir cellulaire et l’évolution tumorale. L’étude a été menée sur deux lignées cellulaires provenant du même patient : SW480 (tumeur primaire) et SW620 (invasion ganglionnaire), aussi utilisées pour la réalisation de greffes sous cutanées sur le modèle murin Nude. De plus, la présence de principales protéines des NTs (TrkB) et de l’autophagie (LC3) a été analysée dans les tissus de patients. Des travaux précédents menés sur des cultures de CCR ont montré que la surexpression de TrkB était associée à la survie cellulaire. Nous avons donc choisi d’inhiber la voie des NTs avec le K252a (100nM). Sur culture cellulaire de CCR, in vitro, l’inactivation de la voie PI3K / AKT, induit une activation de l’autophagie. A l’opposé, le blocage du flux autophagique par une approche pharmacologique (avec la chloroquine, CQ ; 25µM) ou par une approche transcriptomique (siRNA anti-ATG5) induit une suractivation de la signalisation des NTs, via le couple TrkB/BDNF. Ainsi, les deux voies de survie se compensent mutuellement et la double inhibition permet l’amélioration de l’effet des simples traitements. L’utilisation des deux inhibiteurs in vivo induit une réduction spectaculaire du volume tumoral (voire même la disparition dans certains cas). Finalement, la présence de la forme active du TrkB (phospho TrkB) et de la forme active de la LC3 (LC3II), démontrant l’activation de ces deux voies dans les tissus de patients, a été observée. L’ensemble de ces résultats montre que l’activation des voies des NTs et de l’autophagie contribue à la survie des cellules de CCR. L’approche qui consiste à la double inhibition des NTs et de l’autophagie pourrait être un point majeur pour le développement de nouvelles thérapies dans le CCRColorectal cancer (CRC) is the first digestive cancer in occidental countries. Despite effective therapies, cases of resistance and/or recurrence exist. Our laboratory works on two signaling pathways regulating balance between survival and cell death: neurotrophins (NTs, growth factors involved in cancer cells survival) and autophagy (cellular recycling involved in stress resistance). The aim of this study was to investigate relationship between these two pathways and the impact of their inhibition on cell fate and tumor evolution.Studies were performed on two CRC cell lines derived from the same patient: SW480 (primary tumor) and SW620 (node invasion), also used for subcutaneous xenografts on Nude mouse model. In addition, presence of major proteins of NTs (TrkB) and autophagy (LC3) were assessed in patient’s tissues.Previous work showed that TrkB overexpression is associated with pro-survival signaling in CRC cell. So, we choose to inhibit NTs pathway with K252a (100 nM). As expected, inactivation of the PI3K / AKT pathway was observed and CRC cells were able to activate autophagy. At the opposite, blocking autophagic flux by pharmacologic approach (chloroquine; CQ; 25µM) or by transcriptomic approach (siRNA against ATG5) induced over-activation of the NTs pathway, via TrkB/BDNF. Thus, both survival pathways compensate each other. Moreover, dual inhibition allowed improving the effect of single treatment through a significant reduction of metabolic activity. The using of both inhibitors in vivo induces a spectacular reduction of tumor volume (or even disappearance in some cases). Presence of active form of TrkB (phospho TrkB) and active form of LC3 (LC3-II) demonstrating activation of these two pathways, in patient’s tissues have been observed. Taken together, our results showed that activation of NTs and autophagy contribute to CRC cell survival. The approach consisting of dual inhibition of NTs and autophagy could be a major point for new CRC therapies development
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Kobayashi, Nao. "Neurotrophins and the neuronal response to axotomy." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ34565.pdf.
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Cai, Fang. "Expression of neurotrophins in nerve and skin." Thesis, Queen Mary, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322231.
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Bagge, Johan. "TNF-α and neurotrophins in Achilles tendinosis." Doctoral thesis, Umeå universitet, Anatomi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-63660.
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Tenocytes are the principal cells of the human Achilles tendon. In tendinosis, changes in the metabolism and morphology of these cells occur. Neurotrophins are growth factors essential for the development of the nervous system. Tumour necrosis factor alpha (TNF-α) has been found to kill sarcomas but has destructive effects in several major diseases. The two systems have interaction effects and are associated with apoptosis, proliferation, and pain signalling in various diseases. Whether these systems are present in the Achilles tendon and in Achilles tendinosis is unknown. The hypothesis is that the tenocytes produce substances belonging to these systems. In Studies I–III, we show that the potent effects of these substances are also likely to occur in the Achilles tendon. We found tenocyte immunoreactions for the neurotrophins brain-derived neurotrophic factor (BDNF), the nerve growth factor (NGF), the neurotrophin receptor p75, and for TNF-α and both of its receptors, TNFR1 and TNFR2. This occurred in both subjects with painful mid-portion Achilles tendinosis, and in controls. Furthermore, we found mRNA expression for BDNF and TNF-α in tenocytes, which proves that these cells produce these substances. TNFR1 mRNA was also detected for the tenocytes, and TNFR1 immunoreactions were upregulated in tendinosis tendons. This might explain why tenocytes in tendinosis undergo apoptosis more often than in normal tendons. Total physical activity (TPA) level and blood concentration of both soluble TNFR1 and BDNF were measured in Study IV. The results showed that the blood concentration of both factors were similar in subjects with tendinosis and in controls. Nevertheless, the TPA level was related to the blood concentration of sTNFR1 in tendinosis, but not in controls. This relationship should be studied further. The findings of this doctoral thesis show that neurotrophin and TNF-α systems are expressed in the Achilles tendon. We believe that the functions include tissue remodelling, proliferation and apoptosis.
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Bennett, David Lawrence Harvey. "Neurotrophins and sensory neuron development and plasticity." Thesis, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267645.
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GONFLONI, STEFANIA. "Recombinant Antibodies as Structural Probes for Neurotrophins." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 1995. http://hdl.handle.net/2108/76573.
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TIBERI, ALEXIA. "A glial side to the neurotrophin field: studying the effects of neurotrophins on glial cells in the CNS." Doctoral thesis, Scuola Normale Superiore, 2020. http://hdl.handle.net/11384/94548.
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Guiton, Michelle. "Molecular basis of signal transduction by the Trk family of receptor tyrosine kinases." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296366.
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Ringstedt, Thomas. "Neurotrophins during development : overexpression in neural stem cells /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980605ring.
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Wong, Josée F. K. 1972. "Neurotrophins and Trk receptor signaling in cortical development." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33454.
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Neurotrophin-3 was reported to promote cell cycle exit and differentiation of cortical progenitors. We wanted to identify which signaling pathways are responsible for these changes. We observed that chronic treatment of progenitors with BDNF or NT-3, but not NGF resulted in changes in morphology, visualized by MAP2 staining. BDNF treatment led to an increase in primary neurites in calbindin- and calretinin-positive cells when compared with control, but had no effect on proliferation of the proportion of interneurons. We conclude that BDNF enhances the differentiation of cortical neurons. To investigate the role of Trk signaling in cortical neurons, we generated recombinant adenoviruses which carried either wild type or mutated forms of TrkA which inhibit binding and activation of some of its major downstream effectors, namely, SNT, SHC and PLCgamma. Future work should elucidate the role of Trk signaling in central nervous system using these vectors.
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ElShamy, Wael M. "Developmental requirements of neurotrophins in the mammalian nervous system /." Stockholm, 1998. http://diss.kib.ki.se/search/module/diss.cfm?19980916elsh.
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Tirassa, Paola. "Peripherally administered choleocystokinin-8 increases neurotrophins in the brain /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3951-9/.
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Mori, Takuma. "Protein levels of neurotrophins in the developing macaque brain." 京都大学 (Kyoto University), 2004. http://hdl.handle.net/2433/147881.
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Wissman, Anne Marie. "Neurotrophins and seasonal plasticity in the avian song control system /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/10661.
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Nosrat, Christopher A. "Neurotrophins in the development of the gustatory system and teeth /." Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2795-2.
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Iguchi, Fukuichiro. "Cell therapy for application of neurotrophins into the inner ear." Kyoto University, 2004. http://hdl.handle.net/2433/147526.
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Grimsholm, Ola. "Neuropeptides and neurotrophins in arthritis : studies on the human and mouse knee joint." Doctoral thesis, Umeå universitet, Integrativ medicinsk biologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1863.
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Neuropeptides, such as substance P (SP) and bombesin/gastrin-releasing peptide (BN/GRP), and neurotrophins are involved in neuro-immunomodulatory processes and have marked trophic, growth-promoting and inflammation-modulating properties. The impact of these modulators in rheumatoid arthritis (RA) is, however, unclear. An involvement of the innervation, including the peptidergic innervation, is frequently proposed as an important factor for arthritic disease. Many patients with RA, but not all, benefit from treatment with anti-TNF medications. The studies presented here aimed to investigate the roles of neuropeptides, with an emphasis on BN/GRP and SP, and neurotrophins, especially with attention to brain-derived neurotrophic factor (BDNF), in human and murine knee joint tissue. The expression patterns of these substances and their receptors in synovial tissue from patients with either RA or osteoarthritis (OA) were studied in parallel with the levels of these factors in blood and synovial fluid from patients with RA and from healthy controls. Correlation studies were also performed comparing the levels of neuropeptides with those of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)]. Furthermore, the impact of anti-TNF treatment on the levels of BDNF in blood was investigated. In a murine model of RA, the expression of these substances on articular chondrocytes along with their expression in synovial tissue was investigated. The expression of BN/GRP in human synovial tissue was confined to fibroblast-like and mononuclear-like cells whereas SP was detected in nerve-related structures. Receptors for these neuropeptides (GRP-R and NK-1R) were frequently present in blood vessel walls, and on fibroblast-like and mononuclear-like cells. The expression of BDNF and its receptors, p75 neurotrophin receptor and TrkB, was mainly confined to nerve structures. The levels of SP, and particularly those of BN/GRP, in synovial fluid and peripheral blood correlated with the levels of pro-inflammatory cytokines. There were clearly more correlations between SP-BN/GRP and inflammatory parameters than between BDNF and these factors. Plasma levels of BDNF were decreased following anti-TNF-treatment. In the joints of the murine model, there was a marked expression of neurotrophins, neurotrophin receptors and NK-1R/GRP-R in the articular chondrocytes. The expression was down-regulated in the arthritic animals. A neurotrophin system was found to develop in the inflammatory infiltrates of the synovium in the arthritic mice. The results presented suggest that there is a local, and not nerve-related, supply of BN/GRP in the human synovial tissue. Furthermore, BN/GRP and SP have marked effects in the synovial tissue of patients with RA, i.e., there were abundant receptor expressions, and these neuropeptides are, together with cytokines, likely to be involved in the neuro-immunomodulation that occurs in arthritis. The observations do on the whole suggest that the neuropeptides, rather than BDNF, are related to inflammatory processes in the human knee joint. A new effect of anti-TNF treatment; i.e., lowering plasma levels of BDNF, was observed. Severe arthritis, as in the murine model, lead to a decrease in the levels of neurotrophin, and neurotrophin and neuropeptide receptor expressions in the articular cartilage. This fact might be a drawback for the function of the chondrocytes. Certain differences between the expression patterns in the synovial tissue of the murine model and those of human arthritic synovial tissue were noted. It is obvious that local productions in the synovial tissue, nerve-related supply in this tissue and productions in chondrocytes to different extents occur for the investigated substances.
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Kemi, Cecilia. "Studies on neuroimmune interactions in allergic inflammation with focus on neurotrophins /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-885-1/.
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Ilag, Leopold Luna. "Biochemical and biophysical aspects of molecular recognition and signalling by neurotrophins /." Stockholm, 1997. http://diss.kib.ki.se/1997/19971107ilag.
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Zhiou, Jiawei. "The actions of neurotrophins on foetal neuronal survival and phenotype determination." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321768.
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Muhallab, Saad. "T cell production of cytokines, neurotrophins and MHC regulation in autoimmune neuroinflammation /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-260-4.
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Pham, Therese M. "Effects of neonatal handling and enriched environment on neurotrophins and cognitive function /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4362-1/.
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Seehusen, Frauke Antje. "Untersuchungen über Axonopathien und die Rolle des Neurotrophins BDNF bei der kaninen Staupeenzephalitis." Gießen : DVG-Service, 2006. http://d-nb.info/994602146/34.
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Gibbons, Andrew Stuart. "The effects of supplying spinal motoneurons with a constant source of exogenous neurotrophins." Monash University, School of Biological Sciences, 2004. http://arrow.monash.edu.au/hdl/1959.1/9621.
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Jones, Elizabeth Ellen. "NEUROTROPHIN EXPRESSION IN SYMPATHETIC NEURONS: INFLUENCES OF EXOGENOUS NGF AND AFFERENT INPUT." Oxford, Ohio : Miami University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1089903903.
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Matusica, Dusan, and matu0012@flinders edu au. "Regulation of p75NTR Trafficking by Neurotrophins in the NSC-34 Motor Neuron Cell Line." Flinders University. School Of Medicine, 2008. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20080808.115027.
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Neurotrophins are a family of growth factors necessary for the development and maintenance of the nervous system. They produce their effects through receptor mediated signaling mechanisms that are highly regulated by sophisticated intracellular transport networks. The impairment of intracellular trafficking of neurotrophins in motor neurons has been identified as one possible factor in the development of motor neuron diseases, but remains inadequately studied. Aided by advances in imaging technology and the development of more powerful and sensitive detection tools for in-vitro studies, the dynamics of intracellular transport of neurotrophins are beginning to be unraveled. However, a primary limiting factor in the study of neurotrophin-transport dynamics in motor neurons has been the lack of alternative and easily available in-vitro systems able to substitute the often difficult and costly primary motor neuron cultures.
The aim of this project was to develop a suitable motor neuron model using the NSC-34 cell line for the study of receptor mediated trafficking events through endosomal transport pathways. Successful evaluation and characterization of NSC-34 cells for motor neuron specific markers would result in the investigation of the p75 neurotrophin receptor (p75NTR) trafficking pathways in the presence of exogenous neurotrophins, with a variety of confocal imaging techniques.
Chapter 3 describes the optimisation of NSC-34 cell culture conditions through media modification and the development of a suitable growth substrate matrix, which significantly improved cell adhesion, differentiation and the ability to culture the cells for extended time periods in serum free conditions. Quantitative measurements of cell proliferation, culture viability, cell-body size and neurite length are described to highlight the increased value of the cell line for long-term culture and experiments examining a broad range of issues relevant to motor neurons.
In Chapter 4, multiple experimental approaches were used to extensively screen the NSC-34 cell line for the presence of motor neuron-specific markers, neurotrophin receptors and proteins involved in regulation of endosomal transport. This characterization established the presence of a developing motor neuron-like neurotrophin receptor profile (p75NTR, TrkB and TrkC), a genetic marker of developing motor neurons, cholinergic markers, proteins regulating transport within the endosomal pathway, and additional proteins previously shown to directly interact with neurotrophin receptors, including sortilin, and the lipid raft associated ganglioside GT1b. Furthermore, evidence is provided that NSC-34 cells undergo apoptosis in response to exogenous nerve growth factor (NGF) or neurotrophin-3 (NT-3), but not brain derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4). In addition characterization of mouse specific p75NTR antibodies is presented to establish their suitability for internalization studies without altering the binding of exogenous neurotrophins to the receptor.
Subsequent confocal microscopy examination focusing on p75NTR trafficking in Chapter 5 revealed that internalization and intracellular transport of this receptor is regulated by exogenous neurotrophins at the cell surface where ligand binding and internalization occur, and in endosomal compartments where the bulk of receptors and ligands are targeted to their specific destinations. Evidence is provided showing that p75NTR internalization is altered in the presence of NGF, NT-3, or NT-4, but not BDNF, and the receptor is diverted into non-clathrin mediated endosomal pathways in response to NGF but not BDNF. Immunofluorescence confocal microscopy suggests that p75NTR recycles to the plasma membrane in a Rab4 GTPase dependent manner in the absence of neurotrophins. Addition of neurotrophins diverted p75NTR from the recycling Rab4 positive pathway, into EEA-1 positive sorting endosomes in the presence of NGF or NT-3, or lysosomal degradation in the presence of BDNF or NT-4.
This study clearly demonstrates the suitability of the NSC-34 cell line as an alternate in-vitro system for the study of motor neuron biology, particularly the study of neurotrophin receptor trafficking. Taken together the results represented in this study suggest for the first time, that the fate of the p75NTR receptor depends on which neurotrophin is bound. These findings have important implications for understanding the dynamic mechanisms of action of p75NTR in normal neuronal function, and may also offer further insight into the potential role of neurotrophins in the treatment of neurodegenerative diseases.
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Fujita, Kohei. "Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors." Kyoto University, 2012. http://hdl.handle.net/2433/157419.
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Avwenagha, Ovokeloye. "Neurotrophins in the developing and adult rat visual system in vivo and in vitro studies." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341945.
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Bläsing, Holger. "Der Einfluß von proinflammatorischen Zytokinen und Cyclosporin A auf die intra- und extrafollikuläre Expression von Neurotrophinen und ihrer Rezeptoren am Haarfollikel." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2002. http://dx.doi.org/10.18452/14702.
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Der Haarfollikel ist zugleich Quelle und Wirkort verschiedener Zytokine und Neurotrophine. Zytokine können die Expression von Neurotrophinen und ihrer Rezeptoren in verschiedenen extrakutanen Geweben modifizieren. Daher wurde untersucht, ob Zytokine diese Wirkung auch am Haarfollikel entfalten können. Mittels Immunfluoreszenz wurden Kryostatschnitte von Rückenhaut der C57BL/6-Maus dahingehend untersucht, ob die intradermale Injektion von proinflammatorischen Zytokinen (IL-1 beta, TNF-alpha, IFN-gamma), topische Gabe von Dexamethason oder die intraperitoneale Behandlung mit Cyclosporin A (CsA) die intra- und extrafollikuläre Immunreaktivität von NGF, BDNF, NT-4, NT-3 oder ihrer hochaffinen Rezeptoren Trk-A (NGF), Trk-B (BDNF, NT-4), Trk-C (NT-3) oder des niedrigaffinen Rezeptors p75NTR verändert. Alle Haarfollikel befanden sich im Wachstumsstadium des Haarzyklus (Anagen VI). Alle drei untersuchten Zytokine sowie ein Cocktail von IL-1 beta, TNF-alpha und IFN-gamma regulierten die NGF-Immunreaktivität (IR) in der proximalen äußeren Wurzelscheide (ÄWS) und in der Haarmatrix (HM) von Anagen-VI-Haarfollikeln hoch. Der Zytokincocktail regulierte ebenfalls sehr deutlich die NT-3- und NT-4-IR in der murinen Epidermis hoch. Zusätzlich erhöhte dieser Cocktail die NT-4-IR in spezifischen Zellpopulationen von HM und proximaler ÄWS sowie die p75 NTR-Expression in der dermalen Papille. Interessanterweise erhöhte die Behandlung mit CsA in gleicher Weise wie die einzelnen Zytokine und der Zytokincocktail die NGF-IR in HM und proximaler ÄWS. Dexamethason bewirkte in dieser Arbeit keine Veränderungen der Expression von Neurotrophinen bzw. ihrer Rezeptoren. Somit konnte gezeigt werden, daß sowohl bestimmte proinflammatorische Zytokine als auch CsA die intra- und extrafollikuläre Expression von Neurotrophinen und ihrer Rezeptoren verändern.The hair follicle is both, source and target of various cytokines and neurotrophins (NTs), and various cytokines are recognized to alter expression of NTs and their receptors. Therefore I examined, whether cytokines can alter the expression of NTs also in the hair follicle. By means of immunofluorescence, it was investigated on cryostat sections of murine back skin (C57BL/6- mice), whether and how the intradermal injection of proinflammatory cytokines (IL-1 beta, TNF-apha, IFN-gamma, topical dexamethasone or cyclosporin A (CsA) treatment i.g. alter the intra- and extrafollicular immunoreactivity (IR) of NGF, BDNF, NT-4, NT-3 or that of the corresponding high affinity receptors Trk-A (NGF), Trk-B (BDNF, NT-4), Trk-C (NT-3) or their common low affinity receptor p75NTR. All hair follicles were in the growth stage of the hair cycle (Anagen VI). All these cytokines as well as a cocktail of IFN-gamma, IL-1 beta and TNF-alpha increased the NGF-IR in the proximal outer root sheath (ORS) and in the hair matrix (HM) of Anagen VI hair follicles. The cytokine cocktail upregulated NT-3 and NT-4-IR in murine epidermis, increased NT-4-IR in selected cell populations of the HM and the proximal ORS. It enhanced also the p75NTR expression in the dermal papilla. Surprisingly, intraperitoneal treatment with CsA also increased the NGF-IR in HM and ORS, while dexamethasone showed no effect. This demonstrates that selected proinflammatory cytokines and CsA alter the cutaneous intra- and extrafollicular expression of NTs and their receptors.
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Armijo, Weingart Lorena Armijo. "NERVE GROWTH FACTOR INDUCES MITOCHONDRIAL FISSION THAT IS REQUIRED FOR AXON BRANCHING." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/599002.
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NeurosciencePh.D.
The formation of axon collateral branches from the pre-existing shafts of axons is an important aspect of neurodevelopment and the response of the nervous system to injury. Both the actin filament and microtubule components of the cytoskeleton are required for the formation of axon branches. Recent work has begun to shed light on how these two elements of the cytoskeleton are integrated by proteins that functionally or physically link the cytoskeleton. While a number of signaling pathways have been determined as having a role in the formation of axon branches, the complexity of the downstream mechanisms and links to specific signaling pathways remain to be fully determined. Neurotrophins are growth factors that have a multitude of roles in the nervous system. In sensory neurons nerve growth factor (NGF) induces branching through activation of phosphoinositide 3-kinase (PI3K). Recently, mitochondria have emerged as major determinants of the sites of axon branching. In this work we reveal a new role of neurotrophins in mitochondria fission. We report that NGF promote a rapid burst of mitochondria fission, followed by a new steady state of mitochondria length and density. Mek- Erk and PI3k pathways are required for NGF-induced fission. Mek-Erk controls fission through Drp1 activation, while we suggest that PI3K may contributes to the actin dependent aspect of fission. Drp1 mediated fission is required for NGF- induced branching in sensory neurons in vitro and the branching of sensory axons along the developing spinal cord. We reveal that fission is also required for the intra-axonal translation of the actin regulatory proteins Cortactin and Arp2 subunit from the Arp2/3 complex, an important aspect of NGF induced branching. Collectively, these observations reveal a novel role of neurotrophins in mitochondria fission and the formation of collateral branching
Temple University--Theses
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Taylor, R. A. V. "Towards the active site of nerve growth factor : studies on nerve growth factor and related neurotrophins." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388545.
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Pinet, Sandra. "Rôle du transfert des récepteurs des neurotrophines via les exosomes dans l'agressivité du glioblastome et le contrôle du microenvironnement." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0039/document.
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Les glioblastomes (GBM) sont des tumeurs astrocytaires au pronostic défavorable. L’échec des thérapies actuelles (chimio et radiothérapies) est principalement lié à la résistance des cellules souches cancéreuses (CSCs). Ces cellules ont besoin de communiquer en permanence avec leur microenvironnement pour leur survie et pour maintenir une niche favorable à leur développement. Le transfert de matériel entre les CSC, les cellules tumorales et le microenvironnement contribue à l’échappement thérapeutique. Des travaux récents révèlent l’importance des récepteurs aux neurotrophines TrkB et TrkC dans la survie et la croissance des CSC de GBM. Nos travaux préliminaires dans le cancer bronchique démontrent que les récepteurs aux neurotrophines sont transférés aux cellules du microenvironnement via les exosomes afin de les contrôler. Cependant, le mécanisme de diffusion de récepteurs oncogéniques à partir de CSC n’a jamais été étudié. Notre objectif principal était donc de déterminer l’implication des récepteurs des neurotrophines dans le transfert du phénotype agressif des CSC vers les cellules du microenvironnement afin de favoriser la résistance thérapeutique du glioblastome. Nos résultats ont permis d’établir un lien entre le stade de différenciation des cellules tumorales, l’expression des neurotrophines et leur interaction avec le microenvironnement tumoral via les exosomes. Le transfert de TrkB au sein des exosomes joue un rôle clé dans la progression tumorale du GBM et dans l’agressivité cellulaire. Néanmoins, le transfert des récepteurs aux neurotrophines via les exosomes pourrait également être impliqué dans les mécanismes de radiorésistance. Des études menées sur des cellules de GBM humain irradiées et traitées par des exosomes démontrent l’implication de ces derniers dans l’échappement thérapeutique. Parmi les cellules du microenvironnement ciblées par les exosomes, les CSM sont celles qui ont été les moins étudiées bien qu’elles possèdent un tropisme spécifique pour le GBM. Nos travaux démontrent que les exosomes de GBM modifient le phénotype des CSM et augmentent leurs capacités prolifératives et migratoires. La fonction exacte du transfert des récepteurs des neurotrophines devra être analysée dans ces différents modèles afin de préciser son importance dans la physiopathologie du glioblastome et sa progression. L’expression des récepteurs aux neurotrophines dans ces exosomes permet d’envisager leur utilisation en tant que biomarqueurs diagnostiques et/ou pronostiques dans le GBM. Mots clés : Glioblastomes, cellules souches cancéreuses, neurotrophines, TrkB, radiothérapie, cellules souches mésenchymateuses, exosomesGlioblastoma are tumors derived from astrocytes with a dark prognosis. Current therapies fail to inhibit relapses due to radioresistant properties of cancer stem cells (CSC). Communication between CSC and their microenvironment is required for maintain “stem cells niche” and cell survival . The transfer of materials between CSC, tumor cells and microenvironment contributes to therapeutic resistance. In glioma, recent studies reveal the major role of TrkB and TrkC in survival of CSC. Our previous work, in lung cancer, have shown that neurotrophin receptors exhibits a control on microenvironment cells and angiogenesis through exosome transfer. However, similar mechanism of oncogenic receptor transfer from CSC has never been studied. Our main goal was to determine the involvement of neurotrophin receptors in the transfer of biological aggressiveness to microenvironment cells in order to promote therapeutic resistance in glioblastoma. Our findings suggest a relationship between cell differentiation status, expression of neurotrophin receptors and their interaction with the microenvironment through exosomes. TrkB-containing exosomes play a key role in the control of glioblastoma progression and cell aggressiveness. Mechanisms of radioresistance might also be dependent of the transfer of neurotrophin receptors through exosomes. Indeed, our results on irradiated human GBM cells and treated by exosomes demonstrate the involvement of exosome in radioresistance mechanisms. Although mesenchymal stem cells (MSCs) are considered as stromal components of glioblastoma, their communication with CSC, particularly through exosomes, remain largely undefined. Our results show that GBM-derived exosomes modify the phenotype of MSCs and increase their proliferative and migratory abilities. The putative function of neurotrophin receptors transfer should be analyzed in these models to determine their prime role in glioblastoma pathogenesis and progression. This finding suggest that the neurotrophin receptor expression in exosomes could be used as diagnostis and prognosis biomarkers of GBM
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Sayer, Faisal T. "Neurotrophins reduce degeneration of dorsal column sensory and corticospinal motor axons, but not secondary spinal cord damage." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0034/MQ66603.pdf.
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Gowler, Peter. "Investigating the role of neurotrophins in the development of pain responses in animal models of joint pain." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/50660/.
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Background: The chronic joint disease osteoarthritis (OA) represents a significant global problem, not only at the present time, but also for the future. Characterised by articular cartilage degeneration, inflammation of the synovium, and subchondral bone changes, it is the chronic pain associated with OA which presents the most serious consequences. There is a clear need to understand the mechanisms under lying chronic joint pain, and to identify novel therapeutic targets. Two targets which may have therapeutic potential are BDNF and cordycepin. Objectives: The objectives of this thesis are two-fold; firstly to establish a slow progressing murine model of OA that is representative of post-traumatic OA, and secondly to investigate peripheral targets which may modulate chronic OA pain. Methods: Surgical destabilisation of the medial meniscus (DMM) was carried out in adult C57BL/6 mice. Weight bearing asymmetry and hindpaw withdrawal threshold were measured up to 16 weeks post-surgery. Joint pathology was then assessed post-mortem at 16 weeks post-surgery. Another cohort of adult C57BL/6 mice underwent a modified surgical destabilization of the medial meniscus. Pain behaviour and joint pathology outcomes were measured 16 weeks and 20 weeks post-surgery. Osteoarthritis was induced in adult male Sprague Dawley rats via intra-articular injection of monosodium iodoacetate (MIA) or vehicle (50ul 0.9 % saline. A second cohort of male Sprague Dawley rats underwent either meniscal transection (MNX) or sham surgery. Rats then received intra-articular injections of either trkB-fc or human IgG. Pain behaviour was tested up to 3 hours post injection. Adult C57BL/6 mice underwent DMM or sham surgery. Pain behaviour was measured up to 16 weeks post-surgery. From 14 weeks post-surgery mice were orally dosed with either cordycepin or vehicle every two days for two weeks. Joint pathology was then assessed post-mortem at 16 weeks post-surgery. Results:There was a significant increase in weight bearing asymmetry from 13 weeks post DMM surgery in C57BL/6 mice, but no changes in hindpaw withdrawal thresholds. There were also significant increases in chondropathy and synovitis at 16 weeks post-surgery. When the surgical induction of the DMM model was modified there were still significant changes in joint pathology, but no significant changes in pain behaviour. Intra-articular injection of TrkB/fc chimera in rats with established MIA induced joint pain was found to acutely reduce weight bearing asymmetry and increase ipsilateral hindpaw withdrawal thresholds. There was also a significant reduction in pain behaviour in rats with MNX established joint pain when TrkB/fc chimera was injected into the knee joint. Following systemic administration of cordycepin in mice with DMM induced joint pain there was a significant reduction in weightbearing asymmetry when compared to vehicle treated mice. There was also a significant reduction in DMM induced chondropathy, subchondral bone thickening, and osteophytosis in mice treated with cordycepin compared to vehicle treated mice. Conclusions: The changes in pain behaviour outcomes between the traditional and modified DMM, despite similar joint pathology outcomes, suggests a role for meniscal damage as a peripheral driver of OA pain. Localised injection of TrkB/fc chimera into the knee joint of rats with both MIA and MNX induced joint pain was found to acutely reverse joint pain. This implies that peripheral BDNF may be involved in mediating OA joint pain. Oral administration of cordycepin was found to reduce both pain behaviour and joint pathology changes in the DMM model in mice. These results suggest a role for local protein translation underlying both OA chronic pain and joint damage.
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Seehusen, Frauke Antje [Verfasser]. "Untersuchungen über Axonopathien und die Rolle des Neurotrophins BDNF bei der kaninen Staupeenzephalitis / vorgelegt von Frauke Antje Seehusen." Gießen : DVG-Service, 2006. http://d-nb.info/994602146/34.
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Brown, Russell W., Marla K. Perna, Tori L. Schaefer, and Michael T. Williams. "The Effects of Adulthood Nicotine Treatment on D2-Mediated Behavior and Neurotrophins of Rats Neonatally Treated with Quinpirole." Digital Commons @ East Tennessee State University, 2006. https://doi.org/10.1002/syn.20237.
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This study was designed to analyze the effects of nicotine on yawning behavior and neurotrophin content in the hippocampus and frontal cortex of D2-receptor primed female adult Sprague-Dawley rats. Animals were neonatally treated with quinpirole, a dopamine (DA) D2/D3 agonist, from postnatal day 1-21 (P1-21) and raised to P60 and administered nicotine tartarate (0.3 mg/kg free base) or saline twice daily for 14 days. One day after nicotine treatment had ceased, the number of yawns was recorded for 1 h in response to an acute injection of quinpirole (i.p., 100 microg/kg). Yawning is a D2-receptor mediated event. D2-primed rats demonstrated a significant increase in yawning in response to acute quinpirole compared with that of controls, but nicotine did not alleviate this effect. Neonatal quinpirole treatment produced a significant decrease of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the hippocampus that was alleviated by adulthood nicotine treatment. Interestingly, nicotine treatment to controls produced a significant increase of NGF in the frontal cortex, but a significant decrease of both NGF and BDNF in the hippocampus and BDNF in the frontal cortex. The decreases shown in NGF and BDNF is contrary to past findings that have shown nicotine to produce significant increases of hippocampal NGF and BDNF, but these past studies utilized male rats or mice or were performed in vitro. This study shows that nicotine has complex interactions with NGF and BDNF in D2-primed and control animals, and emphasizes the importance of gender differences when analyzing nicotine's effects on neurotrophins.
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Ahmed, Farooque Jamaluddin. "Análise da expressão de neurotrofinas durante a regeneração de nervo periférico de rato por enxerto venoso." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/25/25149/tde-11042015-092834/.
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Análise da expressão de neurotrofinas durante a regeneração de nervo periférico de rato por enxerto venoso Enxertos de veias têm sido empregados para preencher lacunas em nervos periféricos transeccionados para melhor recuperação funcional. No entanto, vários inconvenientes, como a constrição do enxerto secundário foram observados. Uma nova alternativa para esta técnica foi desenvolvida. Simplesmente invertendo a veia de dentro para fora, chamado do Inside- out vein graft. As neurotrofinas são uma família de fatores neurotróficos conhecidos por desempenhar um papel significativo na regeneração de nervos periféricos. A família da neurotrofina é constituído por fator de crescimento nervoso (NGF), fator neurotrófico derivado do cérebro (BDNF), Neurotrofina-3 (NT-3) e Neurotrofina-4 (NT-4). No campo da neurobiologia, vários autores têm utilizado a técnica de PCR a fim de obter mais informações sobre os nervos regenerados. Neste estudo, foi utilizada a técnica de biologia molecular para explorar o papel e o nível das neurotrofinas durante a regeneração de nervos periféricos com enxerto de veia. O nervo isquiático de ratos foi seccionado e reparado com enxerto de veia invertida (IOVG) e técnicas de enxerto de veia padrão (SVG). No grupo controle, os ratos foram operados e o nervo isquiático foi mantido intacto. Os animais foram sacrificados após 6 e 12 semanas e os enxertos foram colhidos para observar o nível das neurotrofinas. Músculos EDL e Sóleo foram excisados e pesados para determinar a diferença de peso entre os grupos. Um pequeno segmento dos cotos distais de ambos os grupos SVG e IOVG também foram excisados e foram processados histologicamente para examinar a quantidade de axónios regenerados. Além disso, um outro pequeno segmento do coto distal foi processado para RT-PCR para analisar o nível das neurotrofinas nesta área.A tecnica do walk track analysis foi realizada para determinar o índice funcional do nervo isquiático nos grupos. Em 6 semanas, não ocorreu crescimento neuronal significativo no coto distal dos dois tipos de enxertos, porém um crescimento foi observado em 12 semanas. Não houve diferença significativa na massa muscular entre IOVG e SVG em ambos os períodos de tempo. No entanto, um aumento significativo na massa muscular foi observado a partir de 6 a 12 semanas nos grupos IOVG e SVG. Um aumento significativo na produção de NT-3 foi observado no grupo de SVG em ambos, enxerto e o coto distal quando comparados a partir de 6 a 12 semanas, no entanto, não houve aumento observado no nível de neurotrofinas dos outros tipos (NGF e NT-4) . Surpreendentemente, não houve aumento significativo da NT-3 no grupo IOVG. Conclui-se que, entre as neurotrofinas avaliadas neste estudo, não há nenhuma diferença significativa no seu nível de RNAm entre os dois grupos, exceto NT-3. Finalmente, uma vez que o nível de RNAm de NT-3 aumenta significativamente entre 6 e 12 semanas no grupo SVG e não no IOVG, observado por estas duas técnicas de nível molecular, estudos adicionais necessitam serem feitos para decifrar o mecanismo exato.Vein grafts have been employed to bridge the gap in transected peripheral nerves to produce better functional recovery. However several disadvantages such as secondary graft constriction were observed and a new alternative to this technique was developed by simply reversing the vein inside out. Both inside out and standard vein grafts were successfully used in recovering the sensory segmental defect in humans. Neurotrophins are a family of eurotrophic factors known to play an important role in the regeneration of peripheral nerves. The neurotrophin family consists of Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotropinh-4 (NT-4). In the neurobiology field, several authors have been using PCR technique in order to gain more information regarding regenerated nerves. In this study, we employed this molecular biology technique to explore the role and level of the neurotrophins during the peripheral nerve regeneration with vein graft. The sciatic nerve of rats were sectioned and repaired with Inside out vein graft (IOVG) and standard vein graft techniques (SVG). In the control group the rats were sham operated wherein the sciatic nerve was kept intact. The animals were euthanized at 6 and 12 weeks and the grafts were harvested to observe the level the neurotrophins. EDL and Sol muscles were excised and measured to determine any weight difference between the groups. A small segment of the distal stumps from both the SVG and IOVG groups were also excised and were subjected to histological process to examine the amount of regenerated axon. In addition, another small segment of the distal stump was processed for RT-PCR to further examine the level of the neurotrophins in this area. At 6 weeks, no significant neuronal growth was observed in the distal stump of both graft types but a distinct growth was seen at 12 weeks. Walk track analysis showed poor motor function recovery in the experimental groups during both time intervals. Morphometric analysis demonstrated no significant differences in the amount of myelination between both the groups. There was no significant difference in the muscle mass between IOVG and SVG in both time periods. However, a significant increase in both the muscle mass was observed from 6 to 12 weeks in the IOVG and SVG groups. A significant increase in the production of NT-3 was observed in SVG group in both the distal stump and graft segment when compared from 6 to 12 weeks; however there was no observed increase in the level of other neurotrophins (NGF and NT-4). Surprisingly, no significant increase of NT-3 was noticed in the IOVG group. We conclude that amongst the neurotrophins evaluated in this study, there is no significant difference in their mRNA level between both groups except NT-3. Also, since mRNA level of NT-3 increases significantly between 6 and 12 weeks in SVG and not in IOVG, it suggests that the mechanism by which these two techniques operate at a molecular level may differ and further studies need to be done to decipher the exact mechanism.
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Saada, Sofiane. "Fonction des neurotrophines et de la neurotensine dans l'oncogénèse lymphocytaire B." Thesis, Limoges, 2015. http://www.theses.fr/2015LIMO0021/document.
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Les neurotrophines sont des facteurs de croissance initialement découverts dans le système nerveux et ayant pour rôle de contrôler la croissance, la prolifération et la survie des cellules neuronales et astrocytaires, mais aussi dans de nombreux autres tissus. Les neurotrophines peuvent interagir avec leurs récepteurs de haute affinité Trks. Les travaux précédemment réalisés au sein de notre équipe ont mis en évidence une boucle de régulation autocrine, en réponse à un stress cellulaire, et ce de façon dépendante des neurotrophines, notamment du BDNF, dans plusieurs lignées lymphocytaires B humaines, à différents stades de différenciation. Les cellules produisent du BDNF qui agit de manière autocrine sur son récepteur spécifique, TrkB. Le transport du BDNF est assuré par la sortiline, une protéine à domaine Vps10. Les neurotrophines sont également synthétisées sous forme de progéniteurs biologiquement actifs, les pro-neurotrophines. Le pro-BDNF interagit avec le récepteur aux neurotrophines à domaine de mort p75NTR, l’interaction du pro-BDNF avec le récepteur p75NTR et de son co-récepteur, la sortiline, induit l’apoptose des lymphocytes B. La sortiline est exprimée dans les lymphocytes B humains, les lignées de lymphocytaires B. La sortiline, également appelée NTSR3, peut lier un autre neuropeptide, la neurotensine (NTS). Identifiée, dans le système nerveux, où elle joue un rôle de neurotransmetteur, impliqué dans l’analgésie et la thermorégulation. Elle est également présente dans le tube digestif, où elle est impliquée dans la régulation de la digestion et le contrôle et de la glycémie. La fonction de la neurotensine est associée à l’activation de la sortiline mais aussi de ses deux récepteurs à protéine G, le récepteur de haute affinité, NTSR1 et le récepteur de faible affinité, NTSR2. La NTS est impliquée dans l’oncogenèse de nombreux cancers solides via sa liaison au récepteur NTSR1 principalement mais également au récepteur NTSR2, notamment dans un modèle de cancer prostatique. Nous avons démontré pour la première fois l’expression de la neurotensine et de ses récepteurs NTSR1 et NTSR2 dans les lymphocytes B humains. Le stress pro-apoptotique induit par la privation sérique favorise une relocalisation des récepteurs NTSR1 et sortiline à la membrane plasmique. Au sein de ces cellules, la neurotensine induit une augmentation de la prolifération et une diminution de l’apoptose. Ces effets de la NTS sont bloqués par l’inhibiteur de NTSR1, le SR48692/Meclinertant®. Les analyses transcriptionnelles ont détecté une surexpression du récepteur NTSR2 au sein des lymphocytes B purifiés de patients ayant une LLC et au niveau des ganglions de patients atteints de lymphomes B en revanche, l’expression de la neurotensine est réduite. La surexpression de NTSR2 induit l’activation transcriptionnelle de TrkB, autre récepteur exprimé par ces lignées comme par les cellules de LLC de patients. La co-localisation de ces 2 récepteurs a été démontrée. Ce complexe protéique induit l’activation des voies de signalisation ERK, p38MAPK et JNK, après traitement par le BDNF, le ligand de TrkB. Ces données suggèrent un phénomène de transactivation entre ces 2 récepteurs, dépendant des métalloprotéases. Le blocage de l’internalisation de ce complexe protéique, induit une augmentation de l’activation des voies de signalisation. Le trafic intra-cellulaire endosomal de ce complexe apparaît perturbé dans les cellules surexprimant NTSR2, ce qui pourrait conduire à son accumulation comme cela est détecté dans les cellules de LLC. Ces cellules leucémiques se caractérisent également par une production d’exosomes contenant le complexe TrkB/NTSR2, sécrété en extra-cellulaire et retrouvé en excès dans le plasma des patients en comparaison à des témoins volontaires sainsNeurotrophins are growth factors, initially discovered in the nervous system and whose functions are implicated in the growth, proliferation and survival of neuronal cells and astrocytes, and also in many other tissues. Neurotrophins can interact with their high-affinity receptors Trks. Previous work in our team showed a neurotrophin-dependent survival autocrine loop in response to cellular stress, including BDNF in several human B cell lines at various stages of B lymphocytes differentiation. These cells produce BDNF which acts in an autocrine manner on its specific tyrosine kinase receptor, TrkB. BDNF transport is provided by a Vps10 domain protein named, sortilin. Neurotrophins are synthesized as biologically active precursors, pro-neurotrophins. The proBDNF may interact with a death domain neurotrophins receptor p75NTR. The interaction of proBDNF with the p75NTR receptor and its co-receptor sortilin, induces B cell apoptosis. Sortilin is expressed in human lymphocytic lines B. Sortilin can bind another neuropeptide, neurotensin (NTS) and also called NTSR3 (Neurotensin Receptor 3). Identified in the nervous system, where it acts as a neurotransmitter involved in analgesia and thermoregulation, NTS is also present in the digestive tract, and involved in the digestion and glucose regulations. Neurotensin functions are associated to the sortilin activation but also its two G-protein coupled receptors, the high and the low affinity receptors, NTSR1 and NTSR2 respectively. NTS is involved in the oncogenesis of many solid cancers, especialy by its binding to the receptor NTSR1 mainly, but also NTSR2 notably in a prostate cancer model. We have demonstrated for the first time the expression of neurotensin and its receptors NTSR1 and NTSR2 in human B lymphocytes. The pro-apoptotic stress induced by serum deprivation promotes relocation NTSR1 receptor sortilin and to the plasma membrane. Within these cells, neurotensin induces increased proliferation and decreased apoptosis. These effects are blocked by the NTSR1 antagonist, SR48692/Meclinertant®. Transcriptional analyzes have detected overexpression of the receptor NTSR2 in purified B cells from patients with CLL and in lymph nodes of B-cell lymphomas patients, in contrast, the expression neurotensin is reduced. Overexpression NTSR2 induced transcriptional activation of TrkB. This receptor is expressed by B cell lines and B cells of CLL patients. The co-localization of these 2 receptors was demonstrated. This protein complex induces the activation of signaling pathways ERK, JNK and p38MAPK, after treatment with BDNF, the TrkB ligand. These data suggest a transactivation between these two receptors, depending to the metalloproteas activation. The internalization blocking of this protein complex, induces its plasma membrane sequestration and induces an increase of the signaling pathways activation. The intracellular endosomal trafficking in cells overexpressing NTSR2 cells, as detected in CLL cells, appears disrupted, which might lead to the NTSR2/TrkB complex accumulation, and releasing to the extracellular environnement. These leukemic cells are also characterized by a production of exosomes containing the TrkB/NTSR2 complex, secreted to the extracellular environement and found in excess in the plasma of patients in comparison to healthy volunteers
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Marchionne, Francesca. "INTRATHECAL DELIVERY OF BDNF TO THE LUMBAR SPINAL CORD VIA IMPLANTED MINI-PUMP RESTORES STEPPING AND MODULATES THE ACTIVITY OF THE LUMBAR SPINAL INTERNEURONS IN A LARGE ANIMAL MODEL OF SPINAL CORD INJURY." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/480625.
Full textAbstract:
BioengineeringPh.D.
Delivery of neurotrophins to the injury site via cellular transplants or viral vectors administration has previously been shown to promote recovery of locomotor behavior in the absence of locomotor training in adult spinalized animals. Viral vectors still pose clinical concerns associated to recombinant genetics and the lack of understanding of how they react with the human immune system. Delivery via graft of autologous fibroblast engineered to produce brain derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3) has been shown as a valuable method; however, the need for multiple invasive surgeries, along with the impossibility of delivering a controlled and constant dosage of protein are serious obstacles to obtaining approval by the FDA. The present study was aimed at evaluating the efficacy of BDNF delivered to the lumbar locomotor centers using a clinically translational delivery method at restoring stepping abilities in a large animal model of spinal cord injury. We wanted to evaluate if intrathecal delivery of BDNF to the lumbar spinal cord would promote a locomotor recovery as effective as delivery to the injury site, even at doses low enough not to trigger the side effects observed at high doses. A programmable and implantable mini-pump was used to intrathecally deliver a 50 ng/day dose of BDNF to the lumbar spinal cord for 35 days after spinal thoracic transection. Kinematic evaluation was conducted before, 3 and 5 weeks after injury/pump implant. Ground reaction forces (GRFs) analysis was performed 5 weeks after injury to evaluate the animals’ ability to weight support during locomotion and standing trials. Results showed that treated cats were capable of executing weight-bearing plantar stepping at all velocities tested (0.3-0.8 m/s). Control cats did not recover stepping ability, especially at higher velocities, and dragged their hind paws on the treadmill. We were also interested in measuring the extent of BDNF diffusion within the lumbar area of the spinal cord and the potential damage to the cord caused by catheter insertion. Immunohistological evaluation showed higher BDNF expression in the dorsal root ganglions, with BDNF Immuno-Histo Chemistry (IHC) extending from L3 to L7 in all treated cats. BDNF was also found within multiple cells of the grey matter, although the levels were not significantly higher than background density. Glial fibrillary acidic protein (GFAP) stain was used to measure the immunohistological reaction of the spinal cord to the implanted catheter, and to establish the safety of the delivery method. Gross examination of the spinal cord post-mortem revealed no damage to the cord or the roots with minimal encapsulation of the catheter/pump. Minimal tissue inflammation was revealed by the GFAP stain, underlying the safety of our method. We also wanted to investigate and characterize changes in the locomotor circuitry induced by BDNF delivery. Comparison of multiunit activity in the lumbar area between BDNF treated and non-treated cats allows a better understanding of the mechanism of action of BDNF on the spinal interneurons. This was accomplished by extracellularly recording lumbar interneuronal firing during air-stepping in a 5 weeks post-injury terminal experiment. The cord was exposed at the lumbar level between the L3 and L7 spinal segments. In-vivo recordings of spinal extracellular signals were conducted using two 64 channels microelectrode arrays inserted at the dorsal root entry zone to depths of ~3000µm and ~1500µm. The ability to record simultaneous activity of multiple single neurons made it possible to study the extent to which spiking activity in a given neuron is related to concurrent ensemble spiking activity. A point process generalized linear model (PP-GLM) approach was used to assess the strength of the connections between spike trains. Interneurons activity was assessed in terms of average firing rate, signal-to-noise ratio (SNR), and number of active units per trial. Although BDNF infusion in the lumbar segments did not show significant effect on strengthening synaptic connections, we did find greater multiunit activity in the treated animals, sign of a potential BDNF-induced increase in interneuronal activation, which could be likely involved in recovery of stepping ability after SCI. Together, findings from these aims demonstrated the therapeutic potential of intrathecal lumbar BDNF delivery in spinalized animals. Constant infusion of BDNF to the locomotor centers promotes locomotor recovery similar to training or delivery to the injury site via cellular transplants after complete SCI. Intrathecal delivery by an implantable/programmable pump is a safe and effective method for delivery of a controlled BDNF dosage; it poses minimal risks to the cord and is clinically usable. Lastly, this study confirmed the major involvement of BDNF in increasing the activity of the interneurons in the locomotor circuitry, opening the door to further investigating the mechanism through which neurotrophins induce recovery of locomotion.
Temple University--Theses
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Seth, J. "Tibial Nerve Stimulation for the management of overactive bladder and the measurement of urinary neurotrophins as a biomarker of response to treatment." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1566640/.
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Segura, Castell Mónica. "Peripheral blood biomarkers in Psychiatric Diseases." Doctoral thesis, Universitat Internacional de Catalunya, 2012. http://hdl.handle.net/10803/83727.
Full textAbstract:
Actually, there is a strong incidence of psychiatric diseases, representing a 13% of total burden diseases and 450 million of people affected. The etiology of psychiatric diseases remains unknown. However, scientific evidences suggest a maldevelopment of nervous system (NS). The diagnosis is inaccurate, and international manuals (ICD-10 and DSM-IV) identify pathologies according to a list of symptoms but no underlying biological cause of disease. The aim of the thesis is to identify potential biomarkers -related to the development of NS- in peripheral blood of psychiatric patients diagnosed as different mental diseases, such as autism spectrum disorders (ASD), schizophrenia and bipolar disorders. It is intended to contribute with the improvement of diagnostic, prognostic and treatment of subjects.
The thesis is divided into 4 chapters: 1) study of neurotrophins in ASD, where the results show the relationship of this family of molecules with the disease, 2) study of Latrophilin-3 (LPHN3) in the TEA, which was obtained in association with lower cognitive level of ASD, 3) study of the Eph-receptor A4 in the pathology of schizophrenia and bipolar disorder, results of which show no association, and finally 4) study of Ankyrin-3 (ANK3) in schizophrenia and bipolar disorder, which shown a relationship with bipolar disorder but not with schizophrenia.Actualment, hi ha una forta incidència de les patologies psiquiàtriques, representant un 13% del total de les malalties i 450 milions de persones afectades. L’etiologia de les patologies psiquiàtriques és desconeguda. Tot i així, evidències científiques suggereixen un mal desenvolupament del sistema nerviós (SN). El diagnòstic és poc precís, i els manuals internacionals (ICD-10 i DSM-IV) identifiquen les patologies d’acord a un llistat de símptomes, però sense cap causa biològica subjacent de la patologia. L’objectiu de la tesi és la identificació de biomarcadors potencials –relacionats en el desenvolupament del SN- en sang perifèrica de pacients diagnosticats amb diferents patologies mentals, com ara els trastorns de l’espectre autista (TEA), esquizofrènia i desordres bipolars. És pretén contribuir amb la millora del diagnòstic, el pronòstic i el tractament de les persones que les pateixen. La tesi s’estructura en 4 capítols: 1) estudi de les neurotrofines en els TEA, on els resultats evidencien la relació d’aquesta família de molècules amb la patologia, 2) estudi de la Latrofilina-3 (LPHN3) en els TEA, on s’ha obtingut associació amb el nivell cognitiu més baix dels TEA, 3) estudi del receptor EPH A4 en les patologies d’esquizofrènia i desordres bipolars, resultats del qual no mostren associació i, per últim 4) estudi de la Ankirina-3 (ANK3) en l’esquizofrènia i els desordres bipolars, en el qual si que es troba una relació amb els desordres bipolars, però no amb l’esquizofrènia.
Actualmente, hay una fuerte incidencia de las patologías psiquiátricas, representando un 13% del total de las enfermedades y 450 millones de personas afectadas. La etiología de las patologías psiquiátricas es desconocida. Aún así, evidencias científicas sugieren un mal desarrollo del sistema nervioso (NS). El diagnóstico es poco preciso, y los manuales internacionales (ICD-10 y DSM-IV) identifican las patologías de acuerdo a un listado de síntomas, pero sin ninguna causa biológica subyacente de la patología. El objetivo de la tesis es la identificación de biomarcadores potenciales –relacionados con el desarrollo del SN- en sangre periférica de pacientes diagnosticados con diferentes patologías mentales, como son los trastornos del espectro autista (TEA), esquizofrenia y desordenes bipolares. Se pretende contribuir en la mejora del diagnóstico, el pronóstico i el tratamiento de las personas que las padecen. La tesis se estructura en 4 capítulos: 1) estudio de las neurotrofinas en los trastornos del espectro autista (TEA), en el cual los resultados evidencian la relación de esta familia de moléculas con la patología, 2) estudio de la Latrofilina-3 (LPHN3) en los TEA, donde se ha obtenido una asociación con el nivel cognitivo más bajo de los TEA, 3) estudio del receptor EPH A4 en las patologías de la esquizofrenia y los desordenes bipolares, resultados del cual no muestran asociación y, por último 4) estudio de la Ankirina-3 (ANK3) en la esquizofrenia y los desordenes bipolares, en el cual si que se ha encontrado una relación con los desordenes bipolares, pero no con la esquizofrenia.