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

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.

Microneurotrophin BNN27 Reduces Astrogliosis and Increases Density of Neurons and Implanted Neural Stem Cell-Derived Cells after Spinal Cord Injury

“…Considering a wider perspective, our study suggests that MNTs can contribute to combinatorial treatments for CNS injuries by simultaneously enhancing cell therapies and modulating the loss of neuronal tissue. MNT contribution in such treatments could be further enhanced by optimizing MNT dosing, exploiting novel MNT designs that target specific neurotrophin receptors [ 67 , 68 ] or utilizing targeted methods to control their spatiotemporal delivery within CNS lesions.…”

The Role of Neurotrophin Signaling in Age-Related Cognitive Decline and Cognitive Diseases

“…In comparison with the action of BDNF-related agonists against neural toxicity, the potential effectiveness of TrkA (or NGF) agonists has not been adequately demonstrated. Rogdakis et al has shown that ENT-A013, a novel NGF mimetic, selectively activates the TrkA receptor [ 53 ]. Due to NGF’s low bioavailability and its impermeability through the blood–brain-barrier, it has been considered that the use of NGF as a potential therapeutic agent against neurodegenerative diseases, including AD, was limited.…”

Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer’s Disease.

“…This led to the development of small molecules that can activate TrkB signaling and mimic the bene cial properties of BDNF, such as 7,8-dihydroxy avone (7, and its derivative CF3CN, some of the best studied BDNF mimetics that can prevent neurotoxicity in vitro and in vivo, enhance learning, prevent memory impairment and promote axonal regeneration [38][39][40][41][42] [43]. Other noticeable examples include GSB-106 [44], LM22A-4 [45] that can promote neurite outgrowth and suppress neuronal death in in-vitro neurodegenerative disease models and a derivative of LM22B-10 that is able to increase survival of iPSC-derived cholinergic neurons after exposure to Aβ [46,47].In addition, derivatives of DHEA, an endogenous neurosteroid produced by neurons and glia in the Central Nervous System (CNS), that bind to and activate neurotrophin receptors have been explored recently [48], including TrkA speci c activator ENT-A013, TrkA and p75NTR activator BNN27, and BNN20 which activates TrkA, TrkB and p75NTR [49,50]and is able to increase BDNF levels through TrkB signaling and exert dopaminergic neuroprotection [51][52][53].…”