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

Biomedicines

卷:10

Marianna Papadopoulou¹  Ioannis Charalampopoulos¹  Achille Gravanis¹  Eleni Papadimitriou¹  Thanasis Rogdakis¹  Despoina Charou¹  Kyriaki Sidiropoulou²  Isbaal Ramos³  Christina Athanasiou⁴  Alexandros Tsengenes⁴  Rebecca C. Wade⁴  Alessia Latorrata⁵  Kyriakos C. Prousis⁵  Theodora Calogeropoulou⁵  Constantina Chalikiopoulou⁵  Theodora Katsila⁵ 

[1] Department of Pharmacology, Medical School, University of Crete, 71003 Heraklion, Greece;

[2] Foundation for Research & Technology-Hellas (IMBB-FORTH), Institute of Molecular Biology & Biotechnology, 70013 Heraklion, Greece;

[3] Innovative Technologies in Biological Systems SL (INNOPROT), 48160 Bizkaia, Spain;

[4] Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany;

[5] National Hellenic Research Foundation, Institute of Chemical Biology, 11635 Athens, Greece;

关键词: neurotrophin;    TrkA neurotrophin receptor;    nerve growth factor;    Alzheimer disease;    amyloid-beta;    neurotrophin mimetic;   

DOI  :  10.3390/biomedicines10030614

来源: DOAJ

【 摘 要 】

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^NTR 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.

【 授权许可】

Unknown