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

• Published in: Biomedicines 2022-03, Vol.10 (3), p.614
• Main Authors: Rogdakis, Thanasis, Charou, Despoina, Latorrata, Alessia, Papadimitriou, Eleni, Tsengenes, Alexandros, Athanasiou, Christina, Papadopoulou, Marianna, Chalikiopoulou, Constantina, Katsila, Theodora, Ramos, Isbaal, Prousis, Kyriakos C, Wade, Rebecca C, Sidiropoulou, Kyriaki, Calogeropoulou, Theodora, Gravanis, Achille, Charalampopoulos, Ioannis
• Format: Article
• Language: English
• Subjects: Affinity; AKT protein; Alzheimer disease; Alzheimer's disease; amyloid-beta; Apoptosis; Binding sites; Bioavailability; Blood-brain barrier; Cell death; Chromatography; Dehydroepiandrosterone; Dorsal root ganglia; Ethanol; Extracellular signal-regulated kinase; Hippocampus; Kinases; Long-term potentiation; Memory; Nerve growth factor; Neurodegenerative diseases; Neuroprotection; Neurotrophic factors; neurotrophin; neurotrophin mimetic; Pathology; Phenotyping; Pheochromocytoma cells; Solvents; Toxicity; TrkA neurotrophin receptor; TrkA protein; TrkA receptors; β-Amyloid
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines10030614

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 p75 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.