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Helena Persson - One of the best experts on this subject based on the ideXlab platform.
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An extended surface of binding to Trk tyrosine kinase receptors in NGF and BDNF allows the engineering of a multifunctional pan-neurotrophin.
The EMBO Journal, 1993Co-Authors: Carlos F Ibanez, Judith Murray-rust, Leodevico L. Ilag, Helena PerssonAbstract:Abstract Neurotrophin-mediated cell survival and differentiation of vertebrate neurons is caused by ligand-specific binding to the Trk family of tyrosine kinase receptors. However, sites in the neurotrophins responsible for the binding to Trk receptors and the mechanisms whereby this interaction results in receptor activation and biological activity are unknown. Here we show that in nerve growth factor (NGF) and brain-derived Neurotrophic factor (BDNF), discontinuous stretches of amino acid residues group together on one side of the neurotrophin dimer forming a continuous surface responsible for binding to and activation of TrkA and TrkB receptors. Two symmetrical surfaces are formed along the two-fold axis of the neurotrophin dimer providing a model for ligand-mediated receptor dimerization. Mutated neurotrophins inducing similar levels of receptor phosphorylation showed different biological activities, suggesting that structural differences in a ligand may result in dissimilar responses in a given tyrosine kinase receptor. Our results allowed us to combine structural elements from NGF, BDNF and neurotrophin-3 to engineer a pan-neurotrophin that efficiently activates all Trk receptors and displays multiple Neurotrophic specificities.
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regulation of neurotrophin and trka trkb and trkc tyrosine kinase receptor messenger rna expression in kindling
Neuroscience, 1993Co-Authors: Johan Bengzon, Helena Persson, Patrik Ernfors, Zaal Kokaia, Merab Kokaia, Giampiero Leanza, Ola G Nilsson, Olle LindvallAbstract:Levels of messenger RNA for nerve growth factor, brain-derived Neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived Neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived Neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived Neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived Neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived Neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived Neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.
Yves-alain Barde - One of the best experts on this subject based on the ideXlab platform.
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Biological Roles of Neurotrophins
Handbook of experimental pharmacology, 1999Co-Authors: Yves-alain BardeAbstract:Neurotrophins are proteins that are structurally related and exert profound effects on cells of the nervous system. Four distinct neurotrophin genes have been identified in mice and in humans that encode for small dimeric, secretory proteins named nerve growth factor (NGF), brain-derived Neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5).
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In vivo effects of neurotrophin-3 during sensory neurogenesis.
Development (Cambridge England), 1996Co-Authors: M. Ockel, Gary R Lewin, Yves-alain BardeAbstract: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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brain derived Neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section
Nature, 1992Co-Authors: Michael Sendtner, Bettina Holtmann, Hans Thoenen, Roland Kolbeck, Yves-alain BardeAbstract:Motoneurons innervating the skeletal musculature were among the first neurons shown to require the presence of their target cells to develop appropriately. But the characterization of molecules allowing motoneuron survival has been difficult. Ciliary Neurotrophic factor prevents the death of motoneurons, but its gene is not expressed during development. Although the presence of a neurotrophin receptor on developing motoneurons has suggested a role for neurotrophins, none could be shown to promote motoneuron survival in vitro. We report here that brain-derived Neurotrophic factor can prevent the death of axotomized motoneurons in newborn rats, suggesting a role for this neurotrophin for motoneuron survival in vivo.
Franz Hefti - One of the best experts on this subject based on the ideXlab platform.
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PHARMACOLOGY OF Neurotrophic FACTORS
Annual Review of Pharmacology and Toxicology, 1997Co-Authors: Franz HeftiAbstract:▪ Abstract The field of Neurotrophic factor pharmacology emerged during the past decade with the discovery that these proteins can counteract neuronal atrophy and death in the adult nervous system. These concepts are being tested in clinical trials. Therapeutic use of Neurotrophic proteins seems practical for diseases of the peripheral nervous system (PNS), where they can be given by systemic administration. For diseases of the CNS, special administration strategies will have to be developed to deliver the Neurotrophic factors into the brain. The development of small molecule mimetics represents an alternative approach that is actively pursued to provide brain-penetrant Neurotrophics.
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Response of embryonic rat hippocampal neurons in culture to neurotrophin-3, brain-derived Neurotrophic factor and basic fibroblast growth factor.
Neuroscience, 1993Co-Authors: Fukuichi Ohsawa, Hans Rudolf Widmer, Beat Knusel, Timothy L. Denton, Franz Hefti, Franz HeftiAbstract:Abstract Primary cultures of rat hippocampal cells have been used to evaluate trophic effects of neurotrophin-3, brain-derived Neurotrophic factor, nerve growth factor, and basic fibroblast growth factor. There was little survival in cultures prepared from embryonic day 17 embryos and grown in defined medium without growth factors. Addition of basic fibroblast growth factor produced a massive increase in the number of neurons present in the cultures seven days after plating. This action reflected proliferation of neuronal precursor cells rather than increased survival of initially plated neurons. Brain-derived Neurotrophic factor was ineffective under these conditions, whereas neurotrophin-3 produced a very small, but statistically significant increase in neuronal survival in the range of 20%. However, hippocampal neurons were responsive to brain-derived Neurotrophic factor and neurotrophin-3 as demonstrated under culture conditions, resulting in survival in absence of the neurotrophins. Acute administration of brain-derived Neurotrophic factor and neurotrophin-3 to hippocampal cultures grown at high density stimulated the hydrolysis of phosphatidylinositol, a response earlier shown to be mediated by tyrosine receptor kinase neurotrophin receptors. Furthermore, when such cultures were grown in presence of neurotrophin-3 rates of glutamate and GABA uptake were increased. In contrast to the findings obtained in cultures of embryonic day 17, cultures prepared from embryonic day 14 or 15 animals were viable in absence of exogenous growth factors. The specific neurotrophin receptor inhibitor, K-252b reduced survival in these cultures and this effect was partly overcome by exogenous neurotrophin-3. Our findings suggest that hippocampal neuron survival at early embryonic stages may involve paracrine neurotrophin mechanisms, whereas the survival of hippocampal neurons of embryonic day 17 is not markedly enhanced by brain-derived Neurotrophic factor or neurotrophin-3. However, at this embryonic stage there is a functional response to both neurotrophins as made evident by the activation of tyrosine kinase receptor-linked signal transduction mechanisms and by the stimulation of transmitter-specific differentiation.
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K-252b selectively potentiates cellular actions and trk tyrosine phosphorylation mediated by neurotrophin-3.
Journal of neurochemistry, 1992Co-Authors: Beat Knusel, Stuart J. Rabin, John W Winslow, David R Kaplan, Karoly Nikolics, Arnon Rosenthal, Franz Hefti, Louis E. Burton, Klaus D. Beck, Franz HeftiAbstract:K-252b, a protein kinase inhibitor, has been shown earlier to inhibit nerve growth factor actions on cholinergic neurons of the basal forebrain. In the present study, K-252b was found to prevent trophic actions of two other neurotrophins, brain-derived Neurotrophic factor, and neurotrophin-3, on central cholinergic and dopaminergic neurons, peripheral sensory neurons, and PC12 pheochromocytoma cells, when used at greater than 2 microM concentration. Comparable actions of nonneurotrophin growth factors were not affected. Surprisingly, at 0.1-100 nM, K-252b selectively enhanced the trophic action of neurotrophin-3 on central cholinergic neurons, peripheral sensory neurons, and PC12 cells. In PC12 cells, K-252b potentiated the neurotrophin-3-induced tyrosine phosphorylation of trk, a protein kinase responsible for transmitting neurotrophin signals. Of the three structurally related nerve growth factor inhibitors, K-252a, K-252b, and staurosporine, only the first two also mediated neurotrophin-3 potentiation. These findings indicate that K-252b generally and selectively potentiates the Neurotrophic action of neurotrophin-3 and suggest that this action involves trk-type neurotrophin receptors.
Kalipada Pahan - One of the best experts on this subject based on the ideXlab platform.
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sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase c pkc mediated activation of camp response element binding protein creb implications for alzheimer disease therapy
Journal of Biological Chemistry, 2013Co-Authors: Grant T Corbett, Kalipada PahanAbstract:Abstract Neurotrophins, such as brain-derived Neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these Neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser133) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by anti-TrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel Neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD.
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sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase c pkc mediated activation of camp response element binding protein creb
2013Co-Authors: Grant T Corbett, Kalipada PahanAbstract:Background: Increase in Neurotrophic factors in the brain is a possible therapeutic approach for different neurodegenerative disorders. Results: Sodium phenylbutyrate, an FDA-approved drug for hyperammonemia, increases Neurotrophic factors in brain cells via the PKC-CREB pathway. Conclusion: These results delineate a novel Neurotrophic property of sodium phenylbutyrate. Significance: Sodium phenylbutyrate may be of therapeutic benefit in neurodegenerative disorders. Neurotrophins, such as brain-derived Neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these Neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser 133 ) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by antiTrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel Neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD. Neurotrophins are a class of small, dimeric growth factors essential for the development, maintenance, and function of the
Olle Lindvall - One of the best experts on this subject based on the ideXlab platform.
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regulation of neurotrophin and trka trkb and trkc tyrosine kinase receptor messenger rna expression in kindling
Neuroscience, 1993Co-Authors: Johan Bengzon, Helena Persson, Patrik Ernfors, Zaal Kokaia, Merab Kokaia, Giampiero Leanza, Ola G Nilsson, Olle LindvallAbstract:Levels of messenger RNA for nerve growth factor, brain-derived Neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived Neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived Neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived Neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived Neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived Neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived Neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.
