TY - GEN ID - 10442/17711 A1 - A1 - Rogdakis, T. A1 - A1 - Charou, D. A1 - A1 - Latorrata, A. A1 - A1 - Papadimitriou, E. A1 - A1 - Tsengenes, A. A1 - A1 - Athanasiou, C. A1 - A1 - Papadopoulou, M. A1 - A1 - Chalikiopoulou, C. A1 - A1 - Katsila, T. A1 - A1 - Ramos, I. A1 - et al. Y1 - 2022/// T1 - Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity JF - Biomedicines VL - 10 IS - 3 SN - 2227-9059 U3 - 10.3390/biomedicines10030614 UR - https://hdl.handle.net/10442/17711 N2 - 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. ER -