Εξειδίκευση τύπου :	Ερευνητικά δεδομένα
Τίτλος:	Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity
Δημιουργός:	Rogdakis, Thanasis Charou, Despoina Latorrata, Alessia Papadimitriou, Eleni Tsengenes, Alexandros Athanasiou, Christina Papadopoulou, Marianna Chalikiopoulou, Constantina [EL] Κατσίλα, Θεοδώρα[EN] Katsila, Theodora Ramos, Isbaal [EL] Προύσης, Κυριάκος[EN] Prousis, Kyriakos Wade, Rebecca C Sidiropoulou, Kyriaki [EL] Καλογεροπούλου, Θεοδώρα[EN] Calogeropoulou, Theodora Gravanis, Achille Charalampopoulos, Ioannis
Ημερομηνία:	2022-03-06
Γλώσσα:	Αγγλικά
Περίληψη:	Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer's Disease (AD) progression. However, its low bioavailability and its blood-brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-β actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid β-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer's Disease, selectively targeting TrkA-mediated pro-survival signals.
Θεματική κατηγορία:	[EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry [EL] Θεραπευτική. Φαρμακολογία[EN] Therapeutics.Pharmacology [EL] Βιολογία (Γενικά)[EN] Biology (General)
Λέξεις-Κλειδιά:	Alzheimer disease TrkA neurotrophin receptor amyloid-beta nerve growth factor neuronal survival neurotrophin neurotrophin mimetic synapse degeneration
EU Grant:	Horizon 2020 Framework Programme, H2020
EU Grant identifier:	Marie Skłodowska-Curie grant agreement No 765704
Κάτοχος πνευματικών δικαιωμάτων:	Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Germany Department of Pharmacology, Medical School, University of Crete, Heraklion, Greece Foundation for Research & Technology-Hellas (IMBB-FORTH), Institute of Molecular Biology & Biotechnology, Heraklion, Greece National Hellenic Research Foundation, Institute of Chemical Biology, Athens, Greece; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany Faculty of Biosciences, Heidelberg University, Heidelberg, Germany Heidelberg Biosciences International Graduate School, Heidelberg University, Heidelberg, Germany Innovative Technologies in Biological Systems SL (INNOPROT), Bizkaia, Spain Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany Department of Biology, University of Crete, Heraklion, Greece
Ηλεκτρονική διεύθυνση με ανοικτή πρόσβαση (link):	https://doi.org/10.3390/biomedicines10030614
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο