Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity
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Abstract:
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.
SEEK ID: https://publications.h-its.org/publications/1470
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
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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. https://doi.org/10.3390/biomedicines10030614
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Created: 7th Mar 2022 at 08:19
Last updated: 5th Mar 2024 at 21:24
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