TY - JOUR A1 - Kittel-Schneider, Sarah A1 - Kenis, Gunter A1 - Schek, Julia A1 - van den Hove, Daniel A1 - Prickaerts, Jos A1 - Lesch, Klaus-Peter A1 - Steinbusch, Harry A1 - Reif, Andreas T1 - Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes JF - Frontiers in Psychiatry N2 - Background: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs. Methods: To examine whether there is a direct effect on the expression of different genes encoding proteins that have been implicated in the pathophysiology of affective disorders, primary astrocyte cell cultures from rats were treated with two different antidepressant drugs, imipramine and escitalopram, and the RNA expression of brain-derived neurotrophic factor (Bdnf), serotonin transporter (5Htt), dopamine transporter (Dat), and endothelial nitric oxide synthase (Nos3) was examined. Results: Stimulation of astroglial cell culture with imipramine, a tricyclic antidepressant, led to a significant increase of the Bdnf RNA level whereas treatment with escitalopram did not. In contrast, 5Htt was not differentially expressed after antidepressant treatment. Finally, neither Dat nor Nos3 RNA expression was detected in cultured astrocytes. Conclusion: These data provide further evidence for a role of astroglial cells in the molecular mechanisms of action of antidepressants. KW - monoamine transporters KW - BDNF KW - geneexpression KW - astrocytes KW - glia KW - depression KW - antidepressant KW - mechanismofaction KW - nitricoxidesynthase Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123627 VL - 3 ER - TY - JOUR A1 - Havik, Bjarte A1 - Degenhardt, Franziska A. A1 - Johansson, Stefan A1 - Fernandes, Carla P. D. A1 - Hinney, Anke A1 - Scherag, André A1 - Lybaek, Helle A1 - Djurovic, Srdjan A1 - Christoforou, Andrea A1 - Ersland, Kari M. A1 - Giddaluru, Sudheer A1 - O'Donovan, Michael C. A1 - Owen, Michael J. A1 - Craddock, Nick A1 - Mühleisen, Thomas W. A1 - Mattheisen, Manuel A1 - Schimmelmann, Benno G. A1 - Renner, Tobias A1 - Warnke, Andreas A1 - Herpertz-Dahlmann, Beate A1 - Sinzig, Judith A1 - Albayrak, Özgür A1 - Rietschel, Marcella A1 - Nöthen, Markus M. A1 - Bramham, Clive R. A1 - Werge, Thomas A1 - Hebebrand, Johannes A1 - Haavik, Jan A1 - Andreassen, Ole A. A1 - Cichon, Sven A1 - Steen, Vidar M. A1 - Le Hellard, Stephanie T1 - DCLK1 Variants Are Associated across Schizophrenia and Attention Deficit/Hyperactivity Disorder JF - PLoS One N2 - Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4x10\(^{-5}\) and 4x10\(^{-6}\), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity. KW - psychosis KW - deficit hyperactivity disorder KW - genome-wide association KW - bipolar disorder KW - VAL66MET polymorphism KW - doublecortine-like KW - genes KW - kinase KW - BDNF KW - endophenotype Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135285 VL - 7 IS - 4 ER - TY - JOUR A1 - Andreska, Thomas A1 - Aufmkolk, Sarah A1 - Sauer, Markus A1 - Blum, Robert T1 - High abundance of BDNF within glutamatergic presynapses of cultured hippocampal neurons JF - Frontiers in Cellular Neuroscience N2 - In the mammalian brain, the neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key factor for synaptic refinement, plasticity and learning. Although BDNF-induced signaling cascades are well known, the spatial aspects of the synaptic BDNF localization remained unclear. Recent data provide strong evidence for an exclusive presynaptic location and anterograde secretion of endogenous BDNF at synapses of the hippocampal circuit. In contrast, various studies using BDNF overexpression in cultured hippocampal neurons support the idea that postsynaptic elements and other dendritic structures are the preferential sites of BDNF localization and release. In this study we used rigorously tested anti-BDNF antibodies and achieved a dense labeling of endogenous BDNF close to synapses. Confocal microscopy showed natural BDNF close to many, but not all glutamatergic synapses, while neither GABAergic synapses nor postsynaptic structures carried a typical synaptic BDNF label. To visualize the BDNF distribution within the fine structure of synapses, we implemented super resolution fluorescence imaging by direct stochastic optical reconstruction microscopy (dSTORM). Two-color dSTORM images of neurites were acquired with a spatial resolution of ~20 nm. At this resolution, the synaptic scaffold proteins Bassoon and Homer exhibit hallmarks of mature synapses and form juxtaposed bars, separated by a synaptic cleft. BDNF imaging signals form granule-like clusters with a mean size of ~60 nm and are preferentially found within the fine structure of the glutamatergic presynapse. Individual glutamatergic presynapses carried up to 90% of the synaptic BDNF immunoreactivity, and only a minor fraction of BDNF molecules was found close to the postsynaptic bars. Our data proof that hippocampal neurons are able to enrich and store high amounts of BDNF in small granules within the mature glutamatergic presynapse, at a principle site of synaptic plasticity. KW - hippocampal neurons KW - synapse structure KW - presynapse KW - synaptic localization KW - BDNF Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119793 SN - 1662-5102 VL - 8 IS - 107 ER - TY - JOUR A1 - Chumak, Tetyana A1 - Rüttiger, Lukas A1 - Lee, Sze Chim A1 - Campanelli, Dario A1 - Zuccotti, Annalisa A1 - Singer, Wibke A1 - Popelář, Jiří A1 - Gutsche, Katja A1 - Geisler, Hyun-Soon A1 - Schraven, Sebastian Philipp A1 - Jaumann, Mirko A1 - Panford-Walsh, Rama A1 - Hu, Jing A1 - Schimmang, Thomas A1 - Zimmermann, Ulrike A1 - Syka, Josef A1 - Knipper, Marlies T1 - BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury JF - Molecular Neurobiology N2 - For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF \(^{Pax2}\) -KO) versus the auditory cortex and hippocampus (BDNF \(^{TrkC}\) -KO). We demonstrate that BDNF \(^{Pax2}\) -KO but not BDNF \(^{TrkC}\) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF \(^{Pax2}\) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF \(^{Pax2}\) -KO, but not of BDNF \(^{TrkC}\) -KO mice. Also, BDNF \(^{Pax2}\) -WT but not BDNF \(^{Pax2}\) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise. KW - Inner hair cell KW - Neurotropathic Factor KW - Hearing-loss KW - Alzheimers-disease KW - low-threshold fibers KW - cochlear nucleus neurons KW - Frequency-response areas KW - Inferior colliculus KW - Environmental enrichment KW - Synaptic plasticity KW - Cortical plasticity KW - BDNF KW - Central hyperactivity KW - High-spontaneous rate KW - Homeostatic plasticity KW - Sound detection threshold Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187341 VL - 53 IS - 8 ER - TY - JOUR A1 - Asthana, Manish Kumar A1 - Brunhuber, Bettina A1 - Mühlberger, Andreas A1 - Reif, Andreas A1 - Schneider, Simone A1 - Herrmann, Martin J. T1 - Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism JF - International Journal of Neuropsychopharmacology N2 - Background: Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. Methods: An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. Results: The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Conclusions: Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans. KW - BDNF KW - brain derived neurotrophic factor KW - fear conditioning KW - genetics memory KW - reconsolidation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166217 VL - 19 IS - 6 ER - TY - JOUR A1 - Dombert, Benjamin A1 - Balk, Stefanie A1 - Lüningschrör, Patrick A1 - Moradi, Mehri A1 - Sivadasan, Rajeeve A1 - Saal-Bauernschubert, Lena A1 - Jablonka, Sibylle T1 - BDNF/trkB induction of calcium transients through Ca\(_{v}\)2.2 calcium channels in motoneurons corresponds to F-actin assembly and growth cone formation on β2-chain laminin (221) JF - Frontiers in Molecular Neuroscience N2 - Spontaneous Ca\(^{2+}\) transients and actin dynamics in primary motoneurons correspond to cellular differentiation such as axon elongation and growth cone formation. Brain-derived neurotrophic factor (BDNF) and its receptor trkB support both motoneuron survival and synaptic differentiation. However, in motoneurons effects of BDNF/trkB signaling on spontaneous Ca\(^{2+}\) influx and actin dynamics at axonal growth cones are not fully unraveled. In our study we addressed the question how neurotrophic factor signaling corresponds to cell autonomous excitability and growth cone formation. Primary motoneurons from mouse embryos were cultured on the synapse specific, β2-chain containing laminin isoform (221) regulating axon elongation through spontaneous Ca\(^{2+}\) transients that are in turn induced by enhanced clustering of N-type specific voltage-gated Ca\(^{2+}\) channels (Ca\(_{v}\)2.2) in axonal growth cones. TrkB-deficient (trkBTK\(^{-/-}\)) mouse motoneurons which express no full-length trkB receptor and wildtype motoneurons cultured without BDNF exhibited reduced spontaneous Ca\(^{2+}\) transients that corresponded to altered axon elongation and defects in growth cone morphology which was accompanied by changes in the local actin cytoskeleton. Vice versa, the acute application of BDNF resulted in the induction of spontaneous Ca\(^{2+}\) transients and Ca\(_{v}\)2.2 clustering in motor growth cones, as well as the activation of trkB downstream signaling cascades which promoted the stabilization of β-actin via the LIM kinase pathway and phosphorylation of profilin at Tyr129. Finally, we identified a mutual regulation of neuronal excitability and actin dynamics in axonal growth cones of embryonic motoneurons cultured on laminin-221/211. Impaired excitability resulted in dysregulated axon extension and local actin cytoskeleton, whereas upon β-actin knockdown Ca\(_{v}\)2.2 clustering was affected. We conclude from our data that in embryonic motoneurons BDNF/trkB signaling contributes to axon elongation and growth cone formation through changes in the local actin cytoskeleton accompanied by increased Ca\(_{v}\)2.2 clustering and local calcium transients. These findings may help to explore cellular mechanisms which might be dysregulated during maturation of embryonic motoneurons leading to motoneuron disease. KW - growth cone KW - BDNF KW - trkB KW - Ca\(_{v}\)2.2 KW - F-actin KW - motor axon Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159094 VL - 10 IS - 346 ER - TY - JOUR A1 - Andreska, Thomas A1 - Lüningschrör, Patrick A1 - Sendtner, Michael T1 - Regulation of TrkB cell surface expression — a mechanism for modulation of neuronal responsiveness to brain-derived neurotrophic factor JF - Cell and Tissue Research N2 - Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of the nervous system in vertebrates. TrkB activation and signaling show substantial differences to other receptor tyrosine kinases of the Trk family that mediate the responses to nerve growth factor and neurotrophin-3. Growing evidence suggests that TrkB cell surface expression is highly regulated and determines the sensitivity of neurons to brain-derived neurotrophic factor (BDNF). This translocation of TrkB depends on co-factors and modulators of cAMP levels, N-glycosylation, and receptor transactivation. This process can occur in very short time periods and the resulting rapid modulation of target cell sensitivity to BDNF could represent a mechanism for fine-tuning of synaptic plasticity and communication in complex neuronal networks. This review focuses on those modulatory mechanisms in neurons that regulate responsiveness to BDNF via control of TrkB surface expression. KW - BDNF KW - TrkB KW - subcellular trafficking KW - transactivation KW - synaptic plasticity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235055 VL - 382 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Hayashi, Kentaro A1 - Störk, Stefan A1 - Scheper, Verena A1 - Lenarz, Thomas A1 - Förster, Carola Y. T1 - The conspicuous link between ear, brain and heart − Could neurotrophin-treatment of age-related hearing loss help prevent Alzheimer's disease and associated amyloid cardiomyopathy? JF - Biomolecules N2 - Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease. KW - Alzheimer's disease KW - amyloid cardiomyopathy KW - heart failure KW - age-related hearing loss KW - neurotrophins KW - blood–brain barrier KW - blood–labyrinth barrier KW - spiral ganglion neuron KW - BDNF KW - GDNF Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241084 SN - 2218-273X VL - 11 IS - 6 ER - TY - THES A1 - Gupta, Rohini T1 - Intracellular self-activation of the TrkB kinase domain causes FAK phosphorylation and disrupts actin filopodia dynamics T1 - Intrazelluläre Selbst-aktivierung der TrkB Kinase induziert FAK Phosphorylierung und verändert die Dynamik von Aktinfilopodien N2 - The tropomysin receptor kinase B (TrkB), the receptor for the neurotrophin brain-derived neurotrophic factor (BDNF), plays an important role in neuronal survival, neuronal differentiation, and cellular plasticity. Conventionally, TrkB activation is induced by binding of BDNF at extracellular sites and subsequent dimerization of receptor monomers. Classical Trk signaling concepts have failed to explain ligand-independent signaling of intracellular TrkB or oncogenic NTRK-fusion proteins. The intracellular activation domain of TrkB consists of a tyrosine kinase core, with three tyrosine (Y) residues at positions 701, 705 and 706, that catalyzes the phosphorylation reaction between ATPγ and tyrosine. The release of cisautoinhibition of the kinase domain activates the kinase domain and tyrosine residues outside of the catalytic domain become phosphorylated. The aim of this study was to find out how ligand-independent activation of TrkB is brought about. With the help of phosphorylation mutants of TrkB, it has been found that a high, local abundance of the receptor is sufficient to activate TrkB in a ligand-independent manner. This self-activation of TrkB was blocked when either the ATP-binding site or Y705 in the core domain was mutated. The vast majority of this self-active TrkB was found at intracellular locations and was preferentially seen in roundish cells, lacking filopodia. Live cell imaging of actin dynamics showed that self-active TrkB changed the cellular morphology by reducing actin filopodia formation. Signaling cascade analysis confirmed that self-active TrkB is a powerful activator of focal adhesion kinase (FAK). This might be the reason why self-active TrkB is able to disrupt actin filopodia formation. The signaling axis from Y705 to FAK could be mimicked by expression of the soluble, cytosolic TrkB kinase domain. However, the signaling pathway was inactive, when the TrkB kinase domain was targeted to the plasmamembrane with the help of artificial myristoylation membrane anchors. A cancer-related intracellular NTRK2-fusion protein (SQSTM1-NTRK2) also underwent constitutive kinase activation. In glioblastoma-like U87MG cells, self-active TrkB kinase reduced cell migration. These constitutive signaling pathways could be fully blocked within minutes by clinically approved, anti-tumorigenic Trk inhibitors. Moreover, this study found evidences for constitutively active, intracellular TrkB in tissue of human grade IV glioblastoma. In conclusion, the data provide an explanation and biological function for selfactive, constitutive TrkB kinase domain signaling, in the absence of a ligand. N2 - Die Rezeptortyrosinkinase TrkB, der Rezeptor für das Neurotrophin brain-derived neurotrophic factor (BDNF), spielt eine wichtige Rolle für das neuronale Überleben, die neuronale Differenzierung und die zelluläre Plastizität. Üblicherweise wird TrkB bei der Bindung von BDNF an extrazellulären Domänen durch Dimerisierung von Rezeptormonomeren aktiviert. Klassische Konzepte der Trk Signalübertragung können jedoch die Liganden-unabhängige Signalübertragung von intrazellulären TrkB- oder Onkogen-aktiven NTRK-Fusionsproteinen nicht erklären. Die intrazelluläre Aktivierungsdomäne von TrkB besitzt eine Tyrosinkinasedomäne mit drei Tyrosin (Y)-Resten an den Positionen 701, 705 und 706. Diese katalysieren die Phosphorylierungsreaktion zwischen ATPγ und Tyrosin. Durch die Enthemmung der cis-Autoinhibition wird die Kinase-Domäne aktiv und Tyrosinreste außerhalb der katalytischen Domäne werden phosphoryliert. Ziel dieser Arbeit war herauszufinden, wie es zur Liganden-unabhängigen Aktivierung von TrkB kommen kann. Mit Hilfe von TrkB-Phosphorylierungsmutanten wurde gefunden, dass eine hohe, lokale Abundanz des Rezeptors ausreicht, um TrkB Liganden-unabhängig zu aktivieren. Diese Selbstaktivierung von TrkB konnte blockiert werden, wenn entweder die ATP-bindende Domäne oder Y705 in der Kinasedomäne mutiert wurden. Die überwiegende Mehrheit dieses selbstaktivierenden TrkB wurde intrazellulär, in rundlichen Zellen ohne Filopodien, gefunden. Live-Zellbildgebung der Aktindynamik zeigte zudem, dass selbstaktives TrkB die Zellmorphologie veränderte, indem es die Bildung von Aktin-Filopodien reduzierte. Die Analyse von Signalkaskaden bestätigte, dass selbstaktives TrkB ein starker Aktivator der Focal Adhesion Kinase (FAK) ist. Dies kann der Grund sein, warum selbstaktives TrkB die Bildung von Aktin-Filopodien zerstört. Die Signalkaskade von Y705 bis FAK konnte durch Expression der löslichen, zytosolischen TrkB-Kinase-Domäne imitiert werden. Der Signalweg war jedoch inaktiv, wenn die TrkB-Kinase-Domäne durch künstliche Myristoylierung an die Plasmamembran gebunden wurde. Ein intrazelluläres NTRK2-Fusionsprotein (SQSTM1-NTRK) zeigte ebenfalls konstitutive Kinaseaktivierung. In Glioblastom-ähnlichen U87MG-Zellen reduzierte die selbstaktive TrkB-Kinase sogar die Zellwanderung. Die konstitutiven Signalwege konnten durch klinisch zugelassene, anti-tumorale Trk-Inhibitoren innerhalb von Minuten vollständig blockiert werden. Darüber hinaus zeigt diese Studie Beweise für konstitutiv-aktives, intrazelluläres TrkB im Gewebe von humanem Glioblastom Grad IV. Die Daten dieser Arbeit geben somit eine Erklärung und eine biologische Funktion für die selbst-aktive, konstitutive Signalübertragung der TrkB-Kinase-Domäne, in Abwesenheit eines Liganden. KW - TrkB KW - self-activation KW - NTRK fusions KW - tyrosine kinase KW - BDNF KW - phosphorylation KW - cancer Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233829 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Böttiger, Gregor A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - FGF/FGFR pathways in multiple sclerosis and in its disease models JF - Cells N2 - Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)\(_{35–55}\)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS. KW - FGF KW - FGFR KW - multiple sclerosis KW - EAE KW - ERK KW - Akt KW - BDNF KW - LINGO-1 KW - SEMA3A Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236594 SN - 2073-4409 VL - 10 IS - 4 ER -