Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity

        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.


DOI: 10.3390/biomedicines10030614

Research Groups: Molecular and Cellular Modeling

Publication type: Journal

Journal: Biomedicines

Citation: Biomedicines 10(3):614

Date Published: 1st Mar 2022

Registered Mode: by DOI

Authors: Thanasis Rogdakis, Despoina Charou, Alessia Latorrata, Eleni Papadimitriou, Alexandros Tsengenes, Christina Athanasiou, Marianna Papadopoulou, Constantina Chalikiopoulou, Theodora Katsila, Isbaal Ramos, Kyriakos C. Prousis, Rebecca C. Wade, Kyriaki Sidiropoulou, Theodora Calogeropoulou, Achille Gravanis, Ioannis Charalampopoulos

Rogdakis, T., Charou, D., Latorrata, A., Papadimitriou, E., Tsengenes, A., Athanasiou, C., Papadopoulou, M., Chalikiopoulou, C., Katsila, T., Ramos, I., Prousis, K. C., Wade, R. C., Sidiropoulou, K., Calogeropoulou, T., Gravanis, A., & Charalampopoulos, I. (2022). Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity. In Biomedicines (Vol. 10, Issue 3, p. 614). MDPI AG.

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Created: 7th Mar 2022 at 08:19

Last updated: 5th Mar 2024 at 21:24

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