Journal articles on the topic 'Neurotrophins'
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1
Gupta, Akash, Jeremias G. Galletti, Zhiyuan Yu, Kevin Burgess, and Cintia S. de Paiva. "A, B, C’s of Trk Receptors and Their Ligands in Ocular Repair." International Journal of Molecular Sciences 23, no. 22 (November 15, 2022): 14069. http://dx.doi.org/10.3390/ijms232214069.
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Neurotrophins are a family of closely related secreted proteins that promote differentiation, development, and survival of neurons, which include nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. All neurotrophins signal through tropomyosin receptor kinases (TrkA, TrkB, and TrkC) which are more selective to NGF, brain-derived neurotrophic factor, and neurotrophin-3, respectively. NGF is the most studied neurotrophin in the ocular surface and a human recombinant NGF has reached clinics, having been approved to treat neurotrophic keratitis. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are less studied neurotrophins in the ocular surface, even though brain-derived neurotrophic factor is well characterized in glaucoma, retina, and neuroscience. Recently, neurotrophin analogs with panTrk activity and TrkC selectivity have shown promise as novel drugs for treating dry eye disease. In this review, we discuss the biology of the neurotrophin family, its role in corneal homeostasis, and its use in treating ocular surface diseases. There is an unmet need to investigate parenteral neurotrophins and its analogs that activate TrkB and TrkC selectively.
2
Krüttgen, Alex, J. Carsten Möller, John V. Heymach, and Eric M. Shooter. "Neurotrophins induce release of neurotrophins by the regulated secretory pathway." Proceedings of the National Academy of Sciences 95, no. 16 (August 4, 1998): 9614–19. http://dx.doi.org/10.1073/pnas.95.16.9614.
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Recent studies have established that neurotrophin synthesis and secretion are regulated by activity and that these factors are involved in activity-dependent processes in the nervous system. Neurotrophins also are known to induce increases in intracellular calcium, a trigger for regulated secretion. This finding raises the possibility that neurotrophins themselves may stimulate regulated secretion of neurotrophins. To address this question, we studied the release of neurotrophins from transfected PC12 cells, a widely used model for neuronal secretion and neurotrophin signal transduction. We found that neurotrophins induced the regulated secretion of brain-derived neurotrophic factor, neurotrophin-3 (NT-3), and neurotrophin-4/5. The effect of brain-derived neurotrophic factor on release of NT-3 could be abolished by REX, a p75 blocking antibody, but not by K252a, an inhibitor of neurotrophin tyrosine kinase receptor (Trk) signaling. The nerve growth factor effect on release of NT-3 could be blocked only by simultaneous application of REX and K252a, suggesting that they are mediated by TrkA as well as p75. Our data show that neurotrophins are able to induce the regulated secretion of neurotrophins and suggest a signal-transducing role for both TrkA and p75 in this process. The neurotrophin-induced release of neurotrophins may be relevant for activity-dependent processes such as synaptic plasticity and memory formation.
3
Dechant, G., S. Biffo, H. Okazawa, R. Kolbeck, J. Pottgiesser, and Y. A. Barde. "Expression and binding characteristics of the BDNF receptor chick trkB." Development 119, no. 2 (October 1, 1993): 545–58. http://dx.doi.org/10.1242/dev.119.2.545.
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Previous studies using transfected cells have indicated that the mammalian receptor tyrosine kinase trkB binds the neurotrophins brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4. However, most studies demonstrating that these neurotrophins prevent the death of embryonic neurons and have specific neuronal receptors have been performed with chick neurons. In order to explore the possibility that trkB is the molecular entity representing the high-affinity receptor for brain-derived neurotrophic factor on embryonic chick neurons, we cloned and expressed a chick trkB cDNA. In situ hybridisation results indicate that the distribution of trkB mRNA in the peripheral nervous system of the developing chick embryo correlates well with the structures known to respond to brain-derived neurotrophic factor. Binding studies performed with a cell line stably transfected with the ctrkB cDNA indicate a dissociation constant for brain-derived neurotrophic factor of 9.9 × 10(−10) M, which is distinctly higher than that found on primary chick sensory neurons (1.5 × 10(−11) M). When binding of brain-derived neurotrophic factor was determined in the presence of other neurotrophins, neurotrophin-3 was found efficiently to prevent the binding of brain-derived neurotrophic factor to both the ctrkB cell line and embryonic sensory neurons. In vitro, neurotrophin-3 at high concentrations completely blocked the survival normally seen with brain-derived neurotrophic factor. Thus, unlike previous cases of receptor occupancy by heterologous neurotrophins (which resulted in agonistic effects), the interaction between the brain-derived neurotrophic factor receptor and neurotrophin-3 on sensory neurons is antagonistic.
4
YIN, Q., G. J. KEMP, and S. P. FROSTICK. "Neurotrophins, Neurones and Peripheral Nerve Regeneration." Journal of Hand Surgery 23, no. 4 (August 1998): 433–37. http://dx.doi.org/10.1016/s0266-7681(98)80117-4.
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Successful peripheral nerve regeneration requires optimal conditions both in the macro-environment and micro-environment. Many methods have been used to improve the macro-environment for the regenerating nerve. However, much less is known about the micro-environment, and in particular the complex neurochemical interactions involved. Several neurotrophic factors have been shown to play an essential trophic role in the development, maintenance and regulation of neuronal function. These include nerve growth factor (NGF) and several recently identified members of the NGF family, namely brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5) and neurotrophin-6 (NT-6). In this review we summarize recent studies of the effects of these neurotrophins on neurones, especially their effects on motor neurones and their axonal outgrowth. We discuss prospects for the future and point out what remains to be understood about the role of neurotrophins to enhance peripheral nerve regeneration.
5
Gatta, Claudia, Valentina Schiano, Chiara Attanasio, Carla Lucini, and Antonio Palladino. "Neurotrophins in Zebrafish Taste Buds." Animals 12, no. 13 (June 23, 2022): 1613. http://dx.doi.org/10.3390/ani12131613.
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The neurotrophin family is composed of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), Neurotrophin 3 (NT3) and NT4. These neurotrophins regulate several crucial functions through the activation of two types of transmembrane receptors, namely p75, which binds all neurotrophins with a similar affinity, and tyrosine kinase (Trk) receptors. Neurotrophins, besides their well-known pivotal role in the development and maintenance of the nervous system, also display the ability to regulate the development of taste buds in mammals. Therefore, the aim of this study is to investigate if NGF, BDNF, NT3 and NT4 are also present in the taste buds of zebrafish (Danio rerio), a powerful vertebrate model organism. Morphological analyses carried out on adult zebrafish showed the presence of neurotrophins in taste bud cells of the oropharyngeal cavity, also suggesting that BDNF positive cells are the prevalent cell population in the posterior part of the oropharyngeal region. In conclusion, by suggesting that all tested neurotrophins are present in zebrafish sensory cells, our results lead to the assumption that taste bud cells in this fish species contain the same homologous neurotrophins reported in mammals, further confirming the high impact of the zebrafish model in translational research.
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Hennigan, A., R. M. O'Callaghan, and Á. M. Kelly. "Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection." Biochemical Society Transactions 35, no. 2 (March 20, 2007): 424–27. http://dx.doi.org/10.1042/bst0350424.
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It is beyond doubt that the neurotrophin family of proteins plays key roles in determining the fate of the neuron, not only during embryonic development, but also in the adult brain. Neurotrophins such as NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) can play dual roles: first, in neuronal survival and death, and, secondly, in activity-dependent plasticity. The neurotrophins manifest their effects by binding to two discrete receptor subtypes: the Trk (tropomyosin receptor kinase) family of RTKs (receptor tyrosine kinases) and the p75NTR (p75 neurotrophin receptor). The differential activation of these receptors by the mature neurotrophins and their precursors, the proneurotrophins, renders analysis of the biological functions of these receptors in the adult brain highly complex. Here, we briefly give a broad review of current knowledge of the roles of neurotrophins in the adult brain, including expression of hippocampal plasticity, neurodegeneration and exercise-induced neuroprotection.
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Kozlov, Evgenii M., Andrey V. Grechko, Yegor S. Chegodaev, Wei-Kai Wu, and Alexander N. Orekhov. "Contribution of Neurotrophins to the Immune System Regulation and Possible Connection to Alcohol Addiction." Biology 9, no. 4 (March 28, 2020): 63. http://dx.doi.org/10.3390/biology9040063.
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The first references to neurotrophic factors date back to the middle of the 20th century when the nerve growth factor (NGF) was first discovered. Later studies delivered a large amount of data on neurotrophic factors. However, many questions regarding neurotrophin signaling still remain unanswered. One of the principal topics in neurotrophin research is their role in the immune system regulation. Another important research question is the possible involvement of neurotrophin signaling in the pathological processes associated with alcoholism. Among known neurotrophins, NT-4 remains the least studied and appears to be involved in alcoholism and chronic stress pathogenesis. In this review we discuss known neurotrophin signaling cascades mediated by different neurotrophin receptors, as well as provide a generalization of the data regarding the influence of neurotrophins NGF, BDNF, and NT-4 on the immune system and their potential contribution to the pathogenesis of alcoholism.
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Bohmwald, Karen, Catalina A. Andrade, Valentina P. Mora, José T. Muñoz, Robinson Ramírez, María F. Rojas, and Alexis M. Kalergis. "Neurotrophin Signaling Impairment by Viral Infections in the Central Nervous System." International Journal of Molecular Sciences 23, no. 10 (May 22, 2022): 5817. http://dx.doi.org/10.3390/ijms23105817.
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Neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), NT-4, and NT-5, are proteins involved in several important functions of the central nervous system. The activation of the signaling pathways of these neurotrophins, or even by their immature form, pro-neurotrophins, starts with their recognition by cellular receptors, such as tropomyosin receptor kinase (Trk) and 75 kD NT receptors (p75NTR). The Trk receptor is considered to have a high affinity for attachment to specific neurotrophins, while the p75NTR receptor has less affinity for attachment with neurotrophins. The correct functioning of these signaling pathways contributes to proper brain development, neuronal survival, and synaptic plasticity. Unbalanced levels of neurotrophins and pro-neurotrophins have been associated with neurological disorders, illustrating the importance of these molecules in the central nervous system. Furthermore, reports have indicated that viruses can alter the normal levels of neurotrophins by interfering with their signaling pathways. This work discusses the importance of neurotrophins in the central nervous system, their signaling pathways, and how viruses can affect them.
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Rochlitzer, S., C. Nassenstein, and A. Braun. "The contribution of neurotrophins to the pathogenesis of allergic asthma." Biochemical Society Transactions 34, no. 4 (July 21, 2006): 594–99. http://dx.doi.org/10.1042/bst0340594.
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The neurotrophins nerve growth factor, brain-derived neurotrophic factor, NT-3 (neurotrophin 3) and NT-4 are known for regulating neuron development, function and survival. Beyond this, neurotrophins were found to exert multiple effects on non-neuronal cells such as immune cells, smooth muscle and epithelial cells. In allergic asthma, airway inflammation, airway obstruction, AHR (airway hyperresponsiveness) and airway remodelling are characteristic features, indicating an intensive interaction between neuronal, structural and immune cells in the lung. In allergic asthma patients, elevated neurotrophin levels in the blood and locally in the lung are commonly observed. Additionally, structural cells of the lung and immune cells, present in the lung during airway inflammation, were shown to be capable of neurotrophin production. A functional relationship between neurotrophins and the main features of asthma was revealed, as airway obstruction, airway inflammation, AHR and airway remodelling were all shown to be stimulated by neurotrophins. The aim of the present review is to provide an overview of neurotrophin sources and target cells in the lung, concerning their possible role as mediators between structural cells, immune cells and neurons, connecting the different features of allergic asthma.
10
Stein, Dan J., Willie M. U. Daniels, Jonathan Savitz, and Brian H. Harvey. "Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of Psychopathology." CNS Spectrums 13, no. 11 (November 2008): 945–49. http://dx.doi.org/10.1017/s1092852900013997.
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ABSTRACTWhile monoaminergic hypotheses of psychopathology remain popular, there has been growing interest in the role of neurotrophins in neuropsychiatric disorders. Basic laboratory work has documented the importance of neurotrophins in neuronal survival and synaptic plasticity, and a range of clinical studies has provided analogous evidence of their role in neuropathology. Work on gene variants in brain-derived neurotrophic factor, and associated changes in structural and function brain imaging, have further contributed to our understanding of this area. Much remains to be done to delineate fully the relevant mechanisms by which brain-derived neurotrophic factor and other neurotrophins contribute to psychopathology, and to develop targeted therapeutic interventions. Nevertheless, the neurotrophin hypothesis has already given impetus to a range of valuable research.
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Blandini, F., L. Rinaldi, C. Tassorelli, G. Sances, M. Motta, A. Samuele, R. Fancellu, G. Nappi, and A. Leon. "Peripheral Levels of BDNF and NGF in Primary Headaches." Cephalalgia 26, no. 2 (February 2006): 136–42. http://dx.doi.org/10.1111/j.1468-2982.2005.01006.x.
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Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), have been implicated in the generation and modulation of pain. To investigate whether alterations in neurotrophin levels can be detected in subjects suffering from nociceptive disorders, such as primary headaches, we determined the peripheral (platelet and plasma) levels of BDNF and NGF in patients suffering from migraine, with or without aura, or cluster headache (CH), in the interictal phase, and in healthy volunteers. All primary headaches patients studied showed significantly decreased platelet levels of BDNF (migraine vs. controls P < 0.001; CH vs. controls P < 0.01), while a selective reduction of platelet NGF was observed in migraine sufferers and not in CH patients compared with control subjects (migraine vs. controls P < 0.001). These changes were not accompanied by significant modifications of neurotrophin plasma levels. Our findings show for the first time that changes in peripheral levels of neurotrophines (BDNF and NGF) occur in patients suffering from different types of primary headaches, suggesting a potential involvement of BDNF and NGF in the pathophysiology of these disorders, and raising the possibility that differences in peripheral neurotrophins may help to distinguish migraine biologically from CH.
12
Gibon, Julien, and Philip A. Barker. "Neurotrophins and Proneurotrophins: Focus on Synaptic Activity and Plasticity in the Brain." Neuroscientist 23, no. 6 (March 17, 2017): 587–604. http://dx.doi.org/10.1177/1073858417697037.
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Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.
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Morisawa, Yasushi, Shinichiro Takayama, Kazuhiko Okushi, Toshiyasu Nakamura, Keiichi Fukuda, Yoshihiro Arakawa, and Yoshiaki Toyama. "QUANTITATION OF NEUROTROPHIN mRNA IN SKELETAL MUSCLE: CHANGES DURING THE PROCESS OF PERIPHERAL NERVE REGENERATION." Journal of Musculoskeletal Research 10, no. 03 (September 2006): 131–40. http://dx.doi.org/10.1142/s0218957706001777.
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Peripheral nerve injury changes the kinetics of neurotrophins. The production of several neurotrophins increases at the site of injury. Although numerous reports have described changes in neurotrophins over time in areas of nerve injury, neurotrophin mRNA is present at very low levels in target tissues, making accurate quantitation difficult. We developed a reverse transcription–polymerase chain reaction/high-performance liquid chromatography (RT-PCR/HPLC) method that enables accurate quantitation of neurotrophin mRNA. We then attempted to quantitate mRNA levels for nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) produced by skeletal muscle innervated by the sciatic nerve following transection and reattachment of the nerve in mice. In addition, wet weights of the muscle were measured and changes in weight over time were determined. The results indicated that neurotrophin production in muscle increases as a result of peripheral nerve denervation due to transection, and decreases with nerve regeneration and reinnervation resulting from reattachment.
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Rabin, Stuart J., Alessia Bachis, and Italo Mocchetti. "Gangliosides Activate Trk Receptors by Inducing the Release of Neurotrophins." Journal of Biological Chemistry 277, no. 51 (October 17, 2002): 49466–72. http://dx.doi.org/10.1074/jbc.m203240200.
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We used NIH-3T3 fibroblasts expressing the different Trk receptors to examine whether GM1 ganglioside and its semisynthetic derivative LIGA20 activate various neurotrophin receptors. GM1 induced autophosphorylation of TrkC more potently than TrkA or TrkB receptors. In contrast, LIGA20 activated TrkB tyrosine phosphorylation only. Therefore, Scatchard analysis was performed to determine whether GM1 binds to TrkC. GM1 failed to displace neurotrophin-3 binding, suggesting that this ganglioside does not act as a ligand for Trk receptors. In addition, GM1 failed to induce autophosphorylation of a chimeric receptor consisting of the extracellular domain of the tumor necrosis factor receptor and the intracellular domain of TrkA, suggesting that GM1 does not affect the tyrosine kinase domain. We next determined whether GM1 induces the release of neurotrophins from fibroblast cells. GM1 induced a rapid and significant increase in the amount of neurotrophin-3, but not other neurotrophins. This effect was independent of the presence of Trk because K252a did not prevent GM1-mediated release of neurotrophin-3. Moreover, GM1-mediated TrkC autophosphorylation was blocked by TrkC-IgG (but not TrkB-IgG) receptor bodies, further suggesting that GM1 activates TrkC by inducing the release of neurotrophin-3. This hypothesis was also tested in cultured cerebellar granule cells. GM1 induced neurotrophin-3 (but not brain-derived neurotrophic factor or nerve growth factor) release. In contrast, LIGA20 increased the secretion of brain-derived neurotrophic factor. Our data show that gangliosides may activate different Trk receptors by differentially affecting the release of neurotrophins.
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Nassenstein, Christina, Armin Braun, Veit Johannes Erpenbeck, Marek Lommatzsch, Stephanie Schmidt, Norbert Krug, Werner Luttmann, Harald Renz, and Johann Christian Virchow. "The Neurotrophins Nerve Growth Factor, Brain-derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4 Are Survival and Activation Factors for Eosinophils in Patients with Allergic Bronchial Asthma." Journal of Experimental Medicine 198, no. 3 (August 4, 2003): 455–67. http://dx.doi.org/10.1084/jem.20010897.
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Neurotrophins (nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], neurotrophin [NT]-3, and NT-4) have been observed in elevated concentrations in allergic diseases. Neurotrophin levels are up-regulated endobronchially after allergen challenge. This coincides with an influx of activated eosinophils into the bronchial lumen. These eosinophils have an increased viability and CD69 expression 18 h after segmental allergen provocation (SAP) which is not present in peripheral blood. To investigate whether these observations are related we studied the influence of neurotrophins on eosinophil function in allergic asthma. Incubation with NGF, BDNF, NT-3, or NT-4 caused a significant increase in the viability and CD69 expression of isolated eosinophils from bronchoalveolar lavage fluid (BALF) but not from peripheral blood, suggesting a unique sensitivity of endobronchial eosinophils to neurotrophins. To elucidate the underlying mechanisms expression of the neurotrophin receptors p75NTR, trkA, trkB, and trkC on eosinophils was analyzed by RT-PCR and immunocytology. After SAP expression of all neurotrophin receptors was markedly elevated on eosinophils from BALF. Our findings suggest that neurotrophin-mediated activation of bronchial eosinophils might play a role in the regulation of eosinophilic inflammation in allergic asthma.
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Chao, Moses V., Rithwick Rajagopal, and Francis S. Lee. "Neurotrophin signalling in health and disease." Clinical Science 110, no. 2 (January 17, 2006): 167–73. http://dx.doi.org/10.1042/cs20050163.
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Neurotrophins are a unique family of polypeptide growth factors that influence the proliferation, differentiation, survival and death of neuronal and non-neuronal cells. They are essential for the health and well-being of the nervous system. NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin-3) and NT-4 (neurotrophin-4) also mediate additional higher-order activities, such as learning, memory and behaviour, in addition to their established functions for cell survival. The effects of neurotrophins depend upon their levels of availability, their affinity of binding to transmembrane receptors and the downstream signalling cascades that are stimulated after receptor activation. Alterations in neurotrophin levels have been implicated in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, as well as psychiatric disorders, including depression and substance abuse. Difficulties in administering trophic factors have led to the consideration of using small molecules, such as GPCR (G-protein-coupled receptor) ligands, which can participate in transactivation events. In this review, we consider the signalling pathways activated by neurotrophins in both health and disease states.
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Bonanni, Roberto, Ida Cariati, Umberto Tarantino, Giovanna D’Arcangelo, and Virginia Tancredi. "Physical Exercise and Health: A Focus on Its Protective Role in Neurodegenerative Diseases." Journal of Functional Morphology and Kinesiology 7, no. 2 (April 29, 2022): 38. http://dx.doi.org/10.3390/jfmk7020038.
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Scientific evidence has demonstrated the power of physical exercise in the prevention and treatment of numerous chronic and/or age-related diseases, such as musculoskeletal, metabolic, and cardiovascular disorders. In addition, regular exercise is known to play a key role in the context of neurodegenerative diseases, as it helps to reduce the risk of their onset and counteracts their progression. However, the underlying molecular mechanisms have not yet been fully elucidated. In this regard, neurotrophins, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glia cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), have been suggested as key mediators of brain health benefits, as they are involved in neurogenesis, neuronal survival, and synaptic plasticity. The production of these neurotrophic factors, known to be increased by physical exercise, is downregulated in neurodegenerative disorders, suggesting their fundamental importance in maintaining brain health. However, the mechanism by which physical exercise promotes the production of neurotrophins remains to be understood, posing limits on their use for the development of potential therapeutic strategies for the treatment of neurodegenerative diseases. In this literature review, we analyzed the most recent evidence regarding the relationship between physical exercise, neurotrophins, and brain health, providing an overview of their involvement in the onset and progression of neurodegeneration.
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Humpel, Christian, Ingrid Strömberg, and Lars Olson. "Expression of Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Neurotrophin-3 mRNAs in Human Cortical Xenografts." Journal of Neural Transplantation and Plasticity 5, no. 4 (1995): 257–64. http://dx.doi.org/10.1155/np.1994.257.
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Trophic factors play an important role in the development of neurons and glia. In order to study the involvement of neurotrophins in human cortical development, human fetal parietal cortical tissue, obtained after early elective abortions, was transplanted to cortical cavities in immunosuppressed rats. Usingin situhybridization it was demonstrated that nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNAs are expressed in developing human cortical xenografts. We conclude that neurotrophins may play a role in human cortical development and rat-derived astroglial cells could be involved in establishing reciprocal “permissive sites”.
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Bonni, Azad, and Michael E. Greenberg. "Neurotrophin Regulation of Gene Expression." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 24, no. 04 (November 1997): 272–83. http://dx.doi.org/10.1017/s0317167100032935.
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ABSTRACT:The neurotrophins comprise a family of secreted proteins that elicit profound responses in cells of the developing and mature vertebrate nervous system including the regulation of neuronal survival and differentiation. The molecular mechanisms by which the neurotrophins exert their effects have been the subject of intense investigation. The neurotrophins elicit responses in neurons via members of the Trk family of receptors and the p75 neurotrophin receptor. Once activated, neurotrophin receptors trigger a large number of biochemical events that propagate the neurotrophin signal from the plasma membrane to the interior of the cell. An important target of the neurotrophin-induced signaling pathways is the nucleus, where neurotrophin-induced signals are coupled to alterations in gene expression. These neurotrophin-induced changes in gene expression are critical for many of. the phenotypic effects of neurotrophins including the regulation of neuronal survival and differentiation.
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Prakash, Y. S., Adeyemi Iyanoye, Binnaz Ay, Carlos B. Mantilla, and Christina M. Pabelick. "Neurotrophin effects on intracellular Ca2+ and force in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 3 (September 2006): L447—L456. http://dx.doi.org/10.1152/ajplung.00501.2005.
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Neurotrophins [e.g., brain-derived neurotrophic factor (BDNF), neurotrophin 4 (NT4)], known to affect neuronal structure and function, are expressed in nonneuronal tissues including the airway. However, their function is unclear. We examined the effect of acute vs. prolonged neurotrophin exposure on regulation of airway smooth muscle (ASM) intracellular Ca2+ concentration ([Ca2+]i): sarcoplasmic reticulum (SR) Ca2+ release and Ca2+ influx (specifically store-operated Ca2+ entry, SOCE). Human ASM cells were incubated for 30 min in medium (control) or 1 or 10 nM BDNF, NT3, or NT4 (acute exposure) or overnight in 1 nM BDNF, NT3, or NT4 (prolonged exposure) and imaged after loading with the Ca2+ indicator fura-2 AM. [Ca2+]i responses to ACh, histamine, bradykinin, and caffeine and SOCE following SR Ca2+ depletion were compared across cell groups. Force measurements were performed in human bronchial strips exposed to neurotrophins. Basal [Ca2+]i, peak responses to all agonists, SOCE, and force responses to ACh and histamine were all significantly enhanced by both acute and prolonged BDNF exposure (smaller effect of NT4) but decreased by NT3. Inhibition of the BDNF/NT4 receptor trkB by K252a prevented enhancement of [Ca2+]i responses. ASM cells showed positive immunostaining for BDNF, NT3, NT4, trkB, and trkC (NT3 receptor). These novel data demonstrate that neurotrophins influence ASM [Ca2+]i and force regulation and suggest a potential role for neurotrophins in airway diseases.
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Reichardt, Louis F. "Neurotrophin-regulated signalling pathways." Philosophical Transactions of the Royal Society B: Biological Sciences 361, no. 1473 (August 2006): 1545–64. http://dx.doi.org/10.1098/rstb.2006.1894.
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Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-γ1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-κB (NF-κB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.
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Neveu, I., and E. Arenas. "Neurotrophins promote the survival and development of neurons in the cerebellum of hypothyroid rats in vivo." Journal of Cell Biology 133, no. 3 (May 1, 1996): 631–46. http://dx.doi.org/10.1083/jcb.133.3.631.
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The development of cerebellar cortex is strongly impaired by thyroid hormone (T3) deficiency, leading to altered migration, differentiation, synaptogenesis, and survival of neurons. To determine whether alteration in the expression of neurotrophins and/or their receptors may contribute to these impairments, we first analyzed their expression using a sensitive RNAse protection assay and in situ hybridization; second, we administered the deficient neurotrophins to hypothyroid animals. We found that early hypothyroidism disrupted the developmental pattern of expression of the four neurotrophins, leading to relatively higher levels of NGF and neurotrophin 4/5 mRNAs and to a severe deficit in NT-3 and brain-derived neurotrophic factor (BDNF) mRNA expression, without alteration in the levels of the full-length tyrosine kinase (trk) B and trkC receptor mRNAs. Grafting of P3 hypothyroid rats with cell lines expressing high levels of neurotrophin 3 (NT-3) or BDNF prevented hypothyroidism-induced cell death in neurons of the internal granule cell layer at P15. In addition, we found that NT-3, but not BDNF, induced the differentiation and/or migration of neurons in the external granule cell layer, stimulated the elaboration of the dendritic tree by Purkinje cells, and promoted the formation of the mature pattern of synaptic afferents to Purkinje cell somas. Thus, our results indicate that both granule and Purkinje neurons require appropriate levels of NT-3 for normal development in vivo and suggest that T3 may regulate the levels of neurotrophins to promote the development of cerebellum.
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Venkatesan, Ramu, Eunhee Ji, and Sun Yeou Kim. "Phytochemicals That Regulate Neurodegenerative Disease by Targeting Neurotrophins: A Comprehensive Review." BioMed Research International 2015 (2015): 1–22. http://dx.doi.org/10.1155/2015/814068.
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Alzheimer’s disease (AD), characterized by progressive dementia and deterioration of cognitive function, is an unsolved social and medical problem. Age, nutrition, and toxins are the most common causes of AD. However, currently no credible treatment is available for AD. Traditional herbs and phytochemicals may delay its onset and slow its progression and also allow recovery by targeting multiple pathological causes by antioxidative, anti-inflammatory, and antiamyloidogenic properties. They also regulate mitochondrial stress, apoptotic factors, free radical scavenging system, and neurotrophic factors. Neurotrophins such as BDNF, NGF, NT3, and NT4/5 play a vital role in neuronal and nonneuronal responses to AD. Neurotrophins depletion accelerates the progression of AD and therefore, replacing such neurotrophins may be a potential treatment for neurodegenerative disease. Here, we review the phytochemicals that mediate the signaling pathways involved in neuroprotection specifically neurotrophin-mediated activation of Trk receptors and members ofp75NTRsuperfamily. We focus on representative phenolic derivatives, iridoid glycosides, terpenoids, alkaloids, and steroidal saponins as regulators of neurotrophin-mediated neuroprotection. Although these phytochemicals have attracted attention owing to theirin vitroneurotrophin potentiating activity, theirin vivoand clinical efficacy trials has yet to be established. Therefore, further research is necessary to prove the neuroprotective effects in preclinical models and in humans.
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Ibanez, C. F., P. Ernfors, T. Timmusk, N. Y. Ip, E. Arenas, G. D. Yancopoulos, and H. Persson. "Neurotrophin-4 is a target-derived neurotrophic factor for neurons of the trigeminal ganglion." Development 117, no. 4 (April 1, 1993): 1345–53. http://dx.doi.org/10.1242/dev.117.4.1345.
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The cellular localization of mRNA for neurotrophin-4 (NT-4), a novel neurotrophic factor, in the developing whisker follicles and skin of the embryonic rat is demonstrated by in situ hybridization. Levels of NT-4 mRNA in the whisker pad decrease between embryonic day 13 (E13) and E20, correlating in time with the onset of naturally occurring neuronal death in the innervating trigeminal ganglion. In addition to NT-4, brain-derived neuotrophic factor (BDNF) mRNA is also shown to be expressed in the rat embryonic whisker follicles although in a different cellular localization, which combined with previous data on the expression of NGF and NT-3 mRNAs, shows that all four neurotrophins are expressed during development of this structure. NT-4 protein is shown to elicit neurite outgrowth from explanted embryonic trigeminal ganglia and to promote neuronal survival of dissociated trigeminal ganglion neurons when cultured during the phase of cell death. NT-4 and NT-3 mainly support different neuronal subpopulations, whereas some NT-4-responsive cells appear to respond also to NGF and BDNF. Analysis of mRNAs for members of the Trk family of neurotrophin receptors in neurons rescued by different neurotrophins demonstrates the presence of distinct neuronal subpopulations that respond to specific combinations of these factors. Based on these results we propose that NT-4, together with the other three neurotrophins, orchestrate the innervation of the different structures of the developing whisker pad by the trigeminal ganglion, acting as target-derived neurotrophic factors for different subpopulations of trigeminal ganglion neurons.
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Shamini Ayyadhury and Klaus Heese. "Neurotrophins - More than Neurotrophic." Current Immunology Reviews 3, no. 3 (August 1, 2007): 189–215. http://dx.doi.org/10.2174/157339507781483504.
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Ahmed, Fozia, Michael D. Paul, and Kalina Hristova. "The biophysical basis of receptor tyrosine kinase ligand functional selectivity: Trk-B case study." Biochemical Journal 477, no. 23 (December 3, 2020): 4515–26. http://dx.doi.org/10.1042/bcj20200671.
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Tropomyosin receptor kinase B (Trk-B) belongs to the second largest family of membrane receptors, Receptor Tyrosine Kinases (RTKs). Trk-B is known to interact with three different neurotrophins: Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-4 (NT-4), and Neurotrophin-3 (NT-3). All three neurotrophins are involved in survival and proliferation of neuronal cells, but each induces distinct signaling through Trk-B. We hypothesize that the different biological effects correlate with differences in the interactions between the Trk-B receptors, when bound to different ligands, in the plasma membrane. To test this hypothesis, we use quantitative FRET to characterize Trk-B dimerization in response to NT-3 and NT-4 in live cells, and compare it to the previously published data for Trk-B in the absence and presence of BDNF. Our study reveals that the distinct Trk-B signaling outcomes are underpinned by both different configurations and different stabilities of the three ligand-bound Trk-B dimers in the plasma membrane.
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Kimata, Hajime. "Passive smoking elevates neurotrophin levels in tears." Human & Experimental Toxicology 23, no. 5 (May 2004): 215–17. http://dx.doi.org/10.1191/0960327104ht445oa.
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The effect of passive smoking on levels of neurotrophin in tears was studied in normal subjects or patients with atopic keratoconjunctivitis (AKC). Basal levels of neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4, in tears were significantly higher in AKC patients than those in normal subjects. Passive smoking had no effect on levels of neurotrophin in tears of normal subjects, while it elevated levels of NGF, BDNF, NT-3 and NT-4 in tears of AKC patients. These results indicate that passive smoking elevates levels of neurotrophin in tears, which in turn may aggravate AKC.
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Bothwell, Mark. "Recent advances in understanding neurotrophin signaling." F1000Research 5 (July 28, 2016): 1885. http://dx.doi.org/10.12688/f1000research.8434.1.
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The nerve growth factor family of growth factors, collectively known as neurotrophins, are evolutionarily ancient regulators with an enormous range of biological functions. Reflecting this long history and functional diversity, mechanisms for cellular responses to neurotrophins are exceptionally complex. Neurotrophins signal through p75NTR, a member of the TNF receptor superfamily member, and through receptor tyrosine kinases (TrkA, TrkB, TrkC), often with opposite functional outcomes. The two classes of receptors are activated preferentially by proneurotrophins and mature processed neurotrophins, respectively. However, both receptor classes also possess neurotrophin-independent signaling functions. Signaling functions of p75NTR and Trk receptors are each influenced by the other class of receptors. This review focuses on the mechanisms responsible for the functional interplay between the two neurotrophin receptor signaling systems.
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Willis, Dianna E., Erna A. van Niekerk, Yukio Sasaki, Mariano Mesngon, Tanuja T. Merianda, Gervan G. Williams, Marvin Kendall, Deanna S. Smith, Gary J. Bassell, and Jeffery L. Twiss. "Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs." Journal of Cell Biology 178, no. 6 (September 4, 2007): 965–80. http://dx.doi.org/10.1083/jcb.200703209.
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Subcellular regulation of protein synthesis requires the correct localization of messenger RNAs (mRNAs) within the cell. In this study, we investigate whether the axonal localization of neuronal mRNAs is regulated by extracellular stimuli. By profiling axonal levels of 50 mRNAs detected in regenerating adult sensory axons, we show that neurotrophins can increase and decrease levels of axonal mRNAs. Neurotrophins (nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3) regulate axonal mRNA levels and use distinct downstream signals to localize individual mRNAs. However, myelin-associated glycoprotein and semaphorin 3A regulate axonal levels of different mRNAs and elicit the opposite effect on axonal mRNA levels from those observed with neurotrophins. The axonal mRNAs accumulate at or are depleted from points of ligand stimulation along the axons. The translation product of a chimeric green fluorescent protein–β-actin mRNA showed similar accumulation or depletion adjacent to stimuli that increase or decrease axonal levels of endogenous β-actin mRNA. Thus, extracellular ligands can regulate protein generation within subcellular regions by specifically altering the localized levels of particular mRNAs.
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Endres, Matthias, Guoping Fan, Lorenz Hirt, Masazumi Fujii, Kohji Matsushita, Xin Liu, Rudolf Jaenisch, and Michael A. Moskowitz. "Ischemic Brain Damage in Mice after Selectively Modifying BDNF or NT4 Gene Expression." Journal of Cerebral Blood Flow & Metabolism 20, no. 1 (January 2000): 139–44. http://dx.doi.org/10.1097/00004647-200001000-00018.
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The neurotrophins and the tyrosine kinase (Trk) B receptor may play a protective role in the pathophysiology of cerebral ischemia. In this study, the authors investigated whether reducing endogenous expression of TrkB-binding neurotrophins modifies the susceptibility to ischemic injury after 1-hour middle cerebral artery occlusion followed by 23 hours of reperfusion in a filament middle cerebral artery occlusion model. Mice lacking both alleles for neurotrophin-4 ( nt4−/−) or deficient in a single allele for brain-derived neurotrophic factor ( bdnf+/−) exhibited larger cerebral infarcts compared to wild-type inbred 129/SVjae mice (68% and 91%, respectively, compared to controls). Moreover, lesions were larger (21%) in nt4−/− mice after permanent middle cerebral artery occlusion. Hence, expression of both NT4 and BDNF, and by inference the TrkB receptor, confers resistance to ischemic injury.
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Seidl, K., A. Buchberger, and C. Erck. "Expression of nerve growth factor and neurotrophin receptors in testicular cells suggest novel roles for neurotrophins outside the nervous system." Reproduction, Fertility and Development 8, no. 7 (1996): 1075. http://dx.doi.org/10.1071/rd9961075.
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The present study was designed to clarify the non-neurotrophic role for neurotrophins in mouse testis. By means of SI nuclease protection assay we could demonstrate that the gene coding for the low-affinity nerve growth factor (NGF) receptor p75NGFR is transiently expressed during germ cell development. Gene expression for p75NGFR was detected in late-meiotic spermatocytes and early spermatids and was found to be co-expressed with trkB and trkC, two tyrosine kinase receptors, commonly regarded as the high-affinity receptors for brain-derived neurotrophic factor and neurotrophin-3. Gene transcripts for the high-affinity NGF receptor trkA were found exclusively in non-germ cells. Isolated Leydig cells, peritubular myoid cells and Sertoli cells, but not germ cells, could be identified as potential testicular NGF sources. Non-germ cells respond after incubation for several days with a sharp induction in NGF synthesis, which is accompanied by a loss of phenotypic expression patterns. The fact that p75NGFR mRNA expression was induced in cultured Sertoli cells and peritubular myoid cells suggests an autocrine mode of NGF action in these cells. Induction of NGF synthesis in cultured Leydig cells could be prevented by the glucocorticoid dexamethasone. Results indicate different roles for the individual neurotrophins in distinct testicular compartments and suggest that these neurotrophins might support testicular functions by signalling between individual cell types in an autocrine and paracrine manner.
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Ockel, M., G. R. Lewin, and Y. A. Barde. "In vivo effects of neurotrophin-3 during sensory neurogenesis." Development 122, no. 1 (January 1, 1996): 301–7. http://dx.doi.org/10.1242/dev.122.1.301.
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The neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 are structurally related proteins regulating the number of neurons in peripheral ganglia of the nervous system. Increased levels of nerve growth factor or of brain-derived neurotrophic factor selectively prevent normally occurring neuronal death, while the targeted elimination of all three genes decreases neuronal numbers. As previous studies indicated that the lack of neurotrophin-3 affects sensory ganglia already during gangliogenesis, the levels of this neurotrophin were increased during selected periods of chick development. We found that early, but not late, applications of neurotrophin-3 lead to a marked decrease in neuronal numbers in peripheral sensory ganglia. This decrease is not seen with BDNF and does not selectively affect subtypes of dorsal root ganglion neurons. It is accompanied by, and might result from, a decrease in the number of proliferating neuroblasts in sensory ganglia of treated embryos.
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Borasio, G. D., A. Markus, A. Wittinghofer, Y. A. Barde, and R. Heumann. "Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons." Journal of Cell Biology 121, no. 3 (May 1, 1993): 665–72. http://dx.doi.org/10.1083/jcb.121.3.665.
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Little is known about the signal transduction mechanisms involved in the response to neurotrophins and other neurotrophic factors in neurons, beyond the activation of the tyrosine kinase activity of the neurotrophin receptors belonging to the trk family. We have previously shown that the introduction of the oncogene product ras p21 into the cytoplasm of chick embryonic neurons can reproduce the survival and neurite-outgrowth promoting effects of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and of ciliary neurotrophic factor (CNTF). To assess the potential signal-transducing role of endogenous ras p21, we introduced function-blocking anti-ras antibodies or their Fab fragments into cultured chick embryonic neurons. The BDNF-induced neurite outgrowth in E12 nodose ganglion neurons was reduced to below control levels, and the NGF-induced survival of E9 dorsal root ganglion (DRG) neurons was inhibited in a specific and dose-dependent fashion. Both effects could be reversed by saturating the epitope-binding sites with biologically inactive ras p21 before microinjection. Surprisingly, ras p21 did not promote the survival of NGF-dependent E12 chick sympathetic neurons, and the NGF-induced survival in these cells was not inhibited by the Fab-fragments. The survival effect of CNTF on ras-responsive ciliary neurons could not be blocked by anti-ras Fab fragments. These results indicate an involvement of ras p21 in the signal transduction of neurotrophic factors in sensory, but not sympathetic or ciliary neurons, pointing to the existence of different signaling pathways not only in CNTF-responsive, but also in neurotrophin-responsive neuronal populations.
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Fu, Xiaoqin, Keling Zang, Zhiwei Zhou, Louis F. Reichardt, and Baoji Xu. "Retrograde Neurotrophic Signaling Requires a Protein Interacting with Receptor Tyrosine Kinases via C2H2 Zinc Fingers." Molecular Biology of the Cell 21, no. 1 (January 2010): 36–49. http://dx.doi.org/10.1091/mbc.e09-04-0321.
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Neurotrophins at axonal terminals signal to cell bodies to regulate neuronal development via signaling endosomes containing activated Trk receptor tyrosine kinases and mitogen-activated protein kinases (MAPKs). Requirements for the formation of signaling endosomes remain, however, poorly characterized. Here we show that a novel Trk-interacting protein, NTRAP (neurotrophic factor receptor–associated protein), plays a crucial role in this signaling process. NTRAP interacts with the Trk intracellular domain through its C2H2 zinc fingers in a kinase-dependent manner. It is associated with vesicles, some of which contain markers for signaling endosomes. Inhibition of NTRAP function suppresses neurotrophin-induced neurite outgrowth in PC12 cells by altering TrkA endocytic traffic, inhibiting the formation of endosomes containing persistently active MAPKs. In compartmentalized sensory neuron cultures, down-regulation of NTRAP abolishes the ability of neurotrophins applied to distal axons to activate the transcription factor adenosine 3′,5′-monophosphate response element-binding protein (CREB) and to promote neuronal survival. We propose that NTRAP regulates retrograde neurotrophic signaling by controlling the formation of signaling endosomes.
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Malenke, Elke, Christiane Dorn, Stefan Wirths, Martin Rudolf Mueller, Lothar Kanz, and Hans-Georg Kopp. "Expression of neurotrophins and their receptors in adult sarcomas." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10562. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10562.
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10562 Background: Neurotrophins (NT) influence proliferation, survival, death, and differentiation by binding Tropomyosin-related kinase (Trk) receptors and p75NTR(CD271). While the three Trk-receptors TrkA, TrkB, and TrkC display specific binding to their ligands, i.e. TrkA to NGF (nerve growth factor), TrkB to BDNF (brain-derived neurotrophic factor), NT4/5 (neurotrophin 4/5) and TrkC to NT3 (neurotrophin 3), CD271 shows low affinity to all neurotrophins. Notably, CD271 has been suggested as marker for the prospective isolation of bone marrow mesenchymal stromal cells (MSC), and rhabdomyosarcomas have previously been found to express neurotrophins and NT receptors. Methods: RNA was isolated from sarcoma cell lines and freshly obtained sarcoma (src) cells from patients after surgical resection. RNA was reverse transcribed and cDNA products underwent PCR analysis with specific primers. Furthermore, cell lines from the same primary tissues were established and treated with doxorubicin. Effects of K252a (Trk receptor inhibitor), Pep5 (CD271-Inhibitor), and neurotrophins on sarcoma cell proliferation and survival were analyzed. Results: An array of freshly obtained clinical src samples (n=10 each subtype) was screened for expression of NT3, NT4/5, BDNF, NGF as well as TrkA, TrkB, TrkC, and CD271. Interestingly, src subtype-specific expression patterns were observed. In the established cell lines, K252a increased doxorubicin-induced tumor cell death, while CD271-Inhibitor Pep5 enhanced proliferation in doxorubicin treated cells, especially under serum free conditions and when combined with BDNF and NGF. Conclusions: NT and NT receptors are expressed on all adult src samples screened in this study. Chemotherapy resistant liposrc as well as myxofibrosrc samples displayed the strongest expression of NT3 as well as TrkB, TrkC, and CD271. The concomitant expression of NT and their receptors suggests autocrine self-stimulation, which may propagate survival, proliferation, and treatment resistance. NT receptor tyrosine kinases may represent an interesting therapeutic target in adult src.
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Gama, Clarissa Severino, Michael Berk, Ana Cristina Andreazza, Flávio Kapczinski, and Paulo Belmonte-de-Abreu. "Serum levels of brain-derived neurotrophic factor and thiobarbituric acid reactive substances in chronically medicated schizophrenic patients: a positive correlation." Revista Brasileira de Psiquiatria 30, no. 4 (December 2008): 337–40. http://dx.doi.org/10.1590/s1516-44462008000400006.
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OBJECTIVE: The neurotrophins, antioxidant enzymes and oxidative markers have reciprocal interactions. This report verified in chronically stable medicated schizophrenic patients whether there are correlations between the serum levels of superoxide dismutase, a key enzyme in the antioxidant defense, thiobarbituric acid reactive substances, a direct index of lipid peroxidation, and brain-derived neurotrophic factor, the most widely distributed neurotrophin. METHOD: Sixty DSM-IV schizophrenic patients were included (43 males, 17 females). Mean age was 34.7 ± 10.8 years, mean age at first episode was 19.8 ± 7.9 years, and mean illness duration was 14.9 ± 8.5 years. Each subject had a blood sample collected for the determination of serum levels of brain-derived neurotrophic factor, thiobarbituric acid reactive substances and superoxide dismutase. RESULTS: Brain-derived neurotrophic factor levels showed a positive correlation with thiobarbituric acid reactive substances levels (r = 0.333, p = 0.009). Brain-derived neurotrophic factor levels were not correlated with superoxide dismutase levels (r = - 0.181, p = 0.166), and superoxide dismutase levels were not correlated with thiobarbituric acid reactive substances levels (r = 0.141, p = 0.284). CONCLUSIONS: The positive correlation between brain-derived neurotrophic factor and thiobarbituric acid reactive substances suggests the need of further investigation on intracellular interactions of neurotrophins, antioxidant enzymes and oxidative markers. In addition, this opens a venue for investigation on treatments for the prevention of neurotoxicity along the course of schizophrenia.
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Caporali, Andrea, and Costanza Emanueli. "Cardiovascular Actions of Neurotrophins." Physiological Reviews 89, no. 1 (January 2009): 279–308. http://dx.doi.org/10.1152/physrev.00007.2008.
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Neurotrophins were christened in consideration of their actions on the nervous system and, for a long time, they were the exclusive interest of neuroscientists. However, more recently, this family of proteins has been shown to possess essential cardiovascular functions. During cardiovascular development, neurotrophins and their receptors are essential factors in the formation of the heart and critical regulator of vascular development. Postnatally, neurotrophins control the survival of endothelial cells, vascular smooth muscle cells, and cardiomyocytes and regulate angiogenesis and vasculogenesis, by autocrine and paracrine mechanisms. Recent studies suggest the capacity of neurotrophins, via their tropomyosin-kinase receptors, to promote therapeutic neovascularization in animal models of hindlimb ischemia. Conversely, the neurotrophin low-affinity p75NTRreceptor induces apoptosis of endothelial cells and vascular smooth muscle cells and impairs angiogenesis. Finally, nerve growth factor looks particularly promising in treating microvascular complications of diabetes or reducing cardiomyocyte apoptosis in the infarcted heart. These seminal discoveries have fuelled basic and translational research and thus opened a new field of investigation in cardiovascular medicine and therapeutics. Here, we review recent progress on the molecular signaling and roles played by neurotrophins in cardiovascular development, function, and pathology, and we discuss therapeutic potential of strategies based on neurotrophin manipulation.
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Bao, Shaowen, Lu Chen, Xiaoxi Qiao, Beat Knusel, and Richard F. Thompson. "Impaired Eye-Blink Conditioning in waggler, a Mutant Mouse With Cerebellar BDNF Deficiency." Learning & Memory 5, no. 4 (September 1, 1998): 355–64. http://dx.doi.org/10.1101/lm.5.4.355.
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In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the wagglercerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning.
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Sakuma, Kunihiro, and Akihiko Yamaguchi. "The Recent Understanding of the Neurotrophin's Role in Skeletal Muscle Adaptation." Journal of Biomedicine and Biotechnology 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/201696.
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This paper summarizes the various effects of neurotrophins in skeletal muscle and how these proteins act as potential regulators of the maintenance, function, and regeneration of skeletal muscle fibers. Increasing evidence suggests that this family of neurotrophic factors influence not only the survival and function of innervating motoneurons but also the development and differentiation of myoblasts and muscle fibers. Muscle contractions (e.g., exercise) produce BDNF mRNA and protein in skeletal muscle, and the BDNF seems to play a role in enhancing glucose metabolism and may act for myokine to improve various brain disorders (e.g., Alzheimer's disease and major depression). In adults with neuromuscular disorders, variations in neurotrophin expression are found, and the role of neurotrophins under such conditions is beginning to be elucidated. This paper provides a basis for a better understanding of the role of these factors under such pathological conditions and for treatment of human neuromuscular disease.
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Fortenbery, Nicole, Rajappa Kenchappa, and Peter A. J. Forsyth. "Neurotrophin signaling and melanoma brain metastases." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13024-e13024. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13024.
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e13024 Background: Adult metastatic brain tumors occur more frequently than primary intracranial neoplasms. Melanoma is the third most common tumor type that metastasizes to the brain. Therefore, elucidating the underlying biological mechanisms of melanoma metastases is critical. Melanocytes and neurons share a neural ectodermal origin, and thus, melanoma may preferentially travel to the brain due to the expression of common neurotrophin receptors, namely p75 neurotrophin receptor (p75NTR) and Trks. Further, high concentrations of neurotrophic factors present in the brain may recruit metastatic melanoma. We hypothesize that neurotrophin signaling through p75NTR is required for the malignant phenotype of melanoma and melanoma brain metastases (MBM). Methods: We investigated the expression of several neutrophin receptors, signaling molecules, and neurotrophins that we hypothesize to be important in the process of MBM. Using 14 malignant melanoma cell lines and two primary MBMs grown under neurosphere conditions, we investigated the expression of these molecules using standard western blotting, flow cytometry, and RT-PCR. We also performed an in depth microarray using of 14 primary MBM patients from Moffitt’s Total Cancer Care project. Results: All melanoma lines examined have robust expression of p75NTR, Trks, and neurotrophins. We find melanoma cell lines resistant to the BRAF inhibitor, vemurafenib, have elevated expression of neurotrophins and neurotrophin receptors when compared to lines sensitive to vemurafenib. We also detect high levels of p75NTR in patient MBM, at both mRNA and protein levels. Finally, we find a significant level of expression of all 11 genes tested by microarray. Conclusions: Previous studies have demonstrated that p75NTR has a role in melanoma cell survival in vitro. Here we demonstrate p75NTR and Trk receptors have high expression in melanoma cell lines and importantly, primary MBM. These data suggest that signaling through neurotophin receptors may be important for melanoma metastases and survival in the brain. Moreover, increased expression by vemurafenib resistant lines may suggest that these cells upregulate the expression of neurotrophin signaling as a means of treatment resistant.
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Endres, Matthias, Guoping Fan, Lorenz Hirt, and Rudolf Jaenisch. "Stroke Damage in Mice after Knocking the Neutrophin-4 Gene into the Brain-Derived Neurotrophic Factor Locus." Journal of Cerebral Blood Flow & Metabolism 23, no. 2 (February 2003): 150–53. http://dx.doi.org/10.1097/01.wcb.0000043949.67811.c6.
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Neurotrophins play a protective role during cerebral ischemia, and mice lacking both alleles for neurotrophin 4 (Nt4−/-) or deficient in a single allele for brain-derived neurotrophic factor (Bdnf−/-) have increased susceptibility to cerebral ischemia. This study directly compared the biologic activities of brain-derived neurotrophic factor (BDNF) and NT4 by replacing the Bdnf coding sequence with the Nt4 sequence (Bdnf+/nt4–ki). Mice expressing one Nt4 allele in place of Bdnf develop 61% bigger lesions after 1-hour middle cerebral artery occlusion compared with wild-type littermates. Physiologic parameters did not contribute to ischemia susceptibility. In conclusion, NT4 is less potent than BDNF in promoting brain survival after stroke.
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Kim, Dong H., Xiurong Zhao, Christina H. Tu, Patrizia Casaccia-Bonnefil, and Moses V. Chao. "Prevention of apoptotic but not necrotic cell death following neuronal injury by neurotrophins signaling through the tyrosine kinase receptor." Journal of Neurosurgery 100, no. 1 (January 2004): 79–87. http://dx.doi.org/10.3171/jns.2004.100.1.0079.
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Object. Neurotrophins prevent the death of neurons during embryonal development and have potential as therapeutic agents. During development, neuronal death occurs only by apoptosis and not by necrosis. Following injury, however, neurons can die by both processes. Data from prior studies have not clearly indicated whether neurotrophins can decrease apoptosis compared with necrosis. The goal of this study was to determine the effect of neurotrophin treatment on each of these processes following injury and to characterize the receptor(s) required. Methods. The authors used an in vitro model of injury with the aid of primary cortical neurons obtained from rat embryos. After 9 days in culture and the elimination of glia, homogeneous and mature neurons were available for experimentation. Noxious stimuli were applied, including radiation, hypoxia, and ischemia. Subsequent cell death by apoptosis or necrosis was noted based on morphological and enzymatic assessments (such as lactate dehydrogenase [LDH] release) and assays for DNA fragmentation. The effect of treatment with nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 was determined. Finally, Western blot analyses were performed to note the neurotrophin receptor status in the neurons (tyrosine kinase receptors [Trks] and p75). The authors studied different stimuli-induced cell death by using different processes. With the application of radiation, cells died primarily by apoptosis, as evidenced by cell shrinkage, the presence of apoptotic bodies, and specific DNA fragmentation. This was a delayed process (> 6 hours) that could be reduced by gene transcription or protein synthesis inhibitors. With ischemia, cells died immediately by necrosis, showing cell enlargement and rupture. Ischemic cell death was not affected by the inhibition of macromolecular synthesis. Hypoxia produced a mixture of the two cell death processes. Both BDNF and neurotrophin-3 demonstrated protection against apoptotic cell death only. Statistically significant decreases of both LDH release and apoptosis-specific DNA fragmentation were noted following radiation and hypoxia, but not for ischemia. Nerve growth factor, unlike the other neurotrophins, did not affect apoptosis because a functional receptor, Trk A, was not expressed by the cortical neurons. There was expression of both Trk B and Trk C, which bind BDNF and neurotrophin-3. Conclusions. These findings have significant clinical implications. Neurotrophins may only be effective in disorders in which apoptosis, and not necrosis, is the major process. Furthermore, the Trk signaling cascade must be activated for this response to occur. Because the expression of these receptors diminishes in adulthood, neurotrophin application may be most appropriate in the pediatric population.
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DUBOVAYA, A. V., S. Ya IAROSHENKO, and O. A. PRILUTSKAYA. "Chronic stress and brain-derived neurotrophic factor." Practical medicine 19, no. 2 (2021): 19–27. http://dx.doi.org/10.32000/2072-1757-2021-2-19-27.
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The article discusses the influence of stress on the development of nervous tissue, in particular, on the synthesis of neurotrophins (by the example of the brain-derived neurotrophic factor (BDNF), as the most studied class representative). The biological functions of BDNF are discussed as well as its influence on neuroplasticity and the mechanisms by which the protection of neurons is carried out. The article covers the relationship of the stress-implementing system (hypothalamic-pituitary-adrenal axis) and its main active agent (cortisol) with the BDNF synthesis system at its various levels: from the inhibition of mRNA formation to the mechanisms of postsynaptic signal transmission. Information is also provided on changes of BDNF levels due to the maternal deprivation. Epigenetic changes under the influence of glucocorticoids are also reported. However, it is not only glucocorticoids that alter the functioning of the neurotrophin system. The article provides examples of the reverse effect, enabling to consider neurotrophins as a substance with an anti-stress function. In conclusion, the authors give examples of activities that, according to research, can stimulate the synthesis of neurotrophic factor in the brain.
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Barouch, Rina, Elena Appel, Gila Kazimirsky, and Chaya Brodie. "Macrophages express neurotrophins and neurotrophin receptors." Journal of Neuroimmunology 112, no. 1-2 (January 2001): 72–77. http://dx.doi.org/10.1016/s0165-5728(00)00408-2.
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Funakoshi, H., J. Frisén, G. Barbany, T. Timmusk, O. Zachrisson, V. M. Verge, and H. Persson. "Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve." Journal of Cell Biology 123, no. 2 (October 15, 1993): 455–65. http://dx.doi.org/10.1083/jcb.123.2.455.
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The neurotrophin family includes NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Previous studies have demonstrated that expression of NGF and its low-affinity receptor is induced in nonneuronal cells of the distal segment of the transected sciatic nerve suggesting a role for NGF during axonal regeneration (Johnson, E. M., M. Taniuchi, and P. S. DeStefano. 1988. Trends Neurosci. 11:299-304). To assess the role of the other neurotrophins and the members of the family of Trk signaling neurotrophin receptors, we have here quantified the levels of mRNAs for BDNF, NT-3, and NT-4 as well as mRNAs for trkA, trkB, and trkC at different times after transection of the sciatic nerve in adult rats. A marked increase of BDNF and NT-4 mRNAs in the distal segment of the sciatic nerve was seen 2 wk after the lesion. The increase in BDNF mRNA was mediated by a selective activation of the BDNF exon IV promoter and adrenalectomy attenuated this increase by 50%. NT-3 mRNA, on the other hand, decreased shortly after the transection but returned to control levels 2 wk later. In Schwann cells ensheathing the sciatic nerve, only trkB mRNA encoding truncated TrkB receptors was detected with reduced levels in the distal part of the lesioned nerve. Similar results were seen using a probe that detects all forms of trkC mRNA. In the denervated gastrocnemius muscle, the level of BDNF mRNA increased, NT-3 mRNA did not change, while NT-4 mRNA decreased. In the spinal cord, only small changes were seen in the levels of neutrophin and trk mRNAs. These results show that expression of mRNAs for neurotrophins and their Trk receptors is differentially regulated after a peripheral nerve injury. Based on these results a model is presented for how the different neurotrophins could cooperate to promote regeneration of injured peripheral nerves.
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Allen, Shelley J., and David Dawbarn. "Clinical relevance of the neurotrophins and their receptors." Clinical Science 110, no. 2 (January 17, 2006): 175–91. http://dx.doi.org/10.1042/cs20050161.
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The neurotrophins are growth factors required by discrete neuronal cell types for survival and maintenance, with a broad range of activities in the central and peripheral nervous system in the developing and adult mammal. This review examines their role in diverse disease states, including Alzheimer's disease, depression, pain and asthma. In addition, the role of BDNF (brain-derived neurotrophic factor) in synaptic plasticity and memory formation is discussed. Unlike the other neurotrophins, BDNF is secreted in an activity-dependent manner that allows the highly controlled release required for synaptic regulation. Evidence is discussed which shows that sequestration of NGF (nerve growth factor) is able to reverse symptoms of inflammatory pain and asthma in animal models. Both pain and asthma show an underlying pathophysiology linked to increases in endogenous NGF and subsequent NGF-dependent increase in BDNF. Conversely, in Alzheimer's disease, there is a role for NGF in the treatment of the disease and a recent clinical trial has shown benefit from its exogenous application. In addition, reductions in BDNF, and changes in the processing and usage of NGF, are evident and it is possible that both NGF and BDNF play a part in the aetiology of the disease process. This highly selective choice of functions and disease states related to neurotrophin function, although in no way comprehensive, illustrates the importance of the neurotrophins in the brain, the peripheral nervous system and in non-neuronal tissues. Ways in which the neurotrophins, their receptors or agonists/antagonists may act therapeutically are discussed.
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Cacialli, Pietro, and Carla Lucini. "Analysis of the Expression of Neurotrophins and Their Receptors in Adult Zebrafish Kidney." Veterinary Sciences 9, no. 6 (June 15, 2022): 296. http://dx.doi.org/10.3390/vetsci9060296.
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Neurotrophins and their receptors are involved in the development and maintenance of neuronal populations. Different reports have shown that all neurotrophin/receptor pathways can also play a role in several non-neuronal tissues in vertebrates, including the kidney. These signaling pathways are involved in different events to ensure the correct functioning of the kidney, such as growth, differentiation, and regulation of renal tubule transport. Previous studies in some fish species have identified the neurotrophins and receptors in the kidney. In this study, for the first time, we compare the expression profiles (mRNA and protein) of all neurotrophin/receptor pathways in the kidney of the adult zebrafish. We quantify the levels of mRNA by using qPCR and identify the expression pattern of each neurotrophin/receptor pathway by in situ hybridization. Next, we detect the proteins using Western blotting and immunohistochemistry. Our results show that among all neurotrophins analyzed, NT-3/TrkC is the most expressed in the glomerule and tubule and in the hematopoietic cells, similar to what has been reported in the mammalian kidney.
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Choi, Jin Gyu, Miran Jeong, Boh Rah Joo, Ji-Hye Ahn, Jeong-Hwa Woo, Dong-Hyun Kim, Myung Sook Oh, and Jung-Hye Choi. "Reduced Levels of Intestinal Neuropeptides and Neurotrophins in Neurotoxin-Induced Parkinson Disease Mouse Models." Journal of Neuropathology & Experimental Neurology 80, no. 1 (October 1, 2020): 15–20. http://dx.doi.org/10.1093/jnen/nlaa113.
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Abstract Intestinal neuropeptides and neurotrophins as endocrine messengers play a key role in the bidirectional gut-brain interaction both in health and disease status. Their alterations in several neurological disorders have been reported, but whether a remarkable change occurs in Parkinson disease (PD) remains unexplored. In this study, we aimed to investigate the levels of 13 neuropeptides and 4 neurotrophins in the intestine of neurotoxin-induced PD mice. The PD mice were obtained by chronic injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or MPTP/probenecid (MPTP/p). The levels of mRNA and protein expression in mouse intestines were measured by using real-time reverse transcription polymerase chain reaction and Western blotting, respectively. We found that the mRNA expression of 2 neuropeptides (cholecystokinin [CCK] and dynorphin A [Dyn A]) and 2 neurotrophins (brain-derived neurotrophic factor [BDNF] and neurotrophin-5) was significantly decreased in the colon of MPTP group compared to the vehicle-treated group. The protein levels of CCK, Dyn A, and BDNF were reduced in the colon of MPTP- or MPTP/p-treated mice compared to those of the vehicle-treated group. These data suggest that the intestinal expression of CCK, Dyn A, and BDNF was significantly reduced in PD animal models, and may play a role in the gut-brain axis in PD.
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Peleshok, J., and H. U. Saragovi. "Functional mimetics of neurotrophins and their receptors." Biochemical Society Transactions 34, no. 4 (July 21, 2006): 612–17. http://dx.doi.org/10.1042/bst0340612.
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Neurotrophins regulate cell survival, death, differentiation and growth. Neurotrophins and their receptors have been validated for pathologies including neurodegenerative disorders of the central nervous system and the peripheral nervous system, certain types of cancers, asthma, inflammation and others. Development of neurotrophin-based therapeutics is important due to the limitations of using whole neurotrophins as pharmacological agents. The use of mimicry has proven to be an alternative. Mimetics can be developed through a number of different approaches. To develop receptor-binding agents, we have used anti-receptor antibody mimicry and neurotrophin mimicry. To develop ligand-binding agents, we have used antiligand antibody mimicry and receptor mimicry. High-throughput screening can be incorporated to complement any of these approaches. The end result is small molecule peptidomimetics with properties favourable over proteins. The present review will offer a general overview of these strategies with a few proven examples from our laboratory.
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Kubanova, A. A., V. A. Smolyannikova, V. V. Chikin, and A. E. Karamova. "Neurotrophins and neuropeptides as inflammatory mediators in case of chronic dermatosis." Vestnik dermatologii i venerologii 90, no. 6 (December 24, 2014): 57–61. http://dx.doi.org/10.25208/0042-4609-2014-90-6-57-61.
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This literature review examines the role of neurotrophins and neuropeptides for the development of skin inflammatory reactions in case of chronic inflammatory dermatoses. The article describes inflammatory effects of neurotrophin, a nerve growth factor, neuropeptide substance P and calcitonin gene-related peptide. Factors affecting the condition of skin innervation and development of inflammation - neurotrophin, a nerve growth factor, amphiregulin, an epidermal growth factor, and semaphorin 3A, a nerve repulsion factor - were examined. Searching for and administering antagonists of proinflammatory effects of neuropeptides, neurotrophins and epidermal growth factor can become new approaches to the treatment of chronic inflammatory dermatoses.