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.…”

Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor, Regulating Neuronal Survival in a Cell Context-Dependent Manner

“…It can also interact with p75NTR, inducing the recruitment of effector proteins RIP2 and TRAF6 to the receptor and the release of RhoGDI in primary granular cells of the cerebellum, as well as inducing neuroprotective effects [17]. Recently, Rogdakis et al showed that ENT-A013, which is a chemically stable and more potent compound than BNN27, selectively activates TrkA receptor and exerts neuroprotective and anti-amyloid actions [20].…”

“…Although it activates both TrkB and p75NTR neurotrophin receptors, it exerts differential signaling and cellular effects in a cell-specific manner, depending on which receptor is expressed and, surprisingly, the species origin-mouse or human-of the neuronal cell. Notably, ENT-A044 is a compound that is structurally similar to ENT-A013, which is a well characterized TrkA activator derived from the same synthetic procedures [20]. However, ENT-A044 cannot activate TrkA, as is obvious from the total absence of phosphorylation of Akt and Erk kinases, which are the most significant downstream signals of the TrkA receptor in TrkA-expressing PC12 cells.…”

“…In parallel, other analogs of the same chemical library were also tested. Western blot analysis revealed that ENT-A044 cannot induce the phosphorylation of kinases Akt and Erk1/2, which are known to be activated upon TrkA activation and have been associated with NGF promotion of cell survival (Figure 1b), while other compounds of similar structure were able to activate these kinases [20]. Thus, considering the inability of ENT-A044 to activate the TrkA receptor, the observed cell death in PC12 is probably mediated by p75NTR.…”

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.…”