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.
Highlights
Endogenous neurotrophic factors constitute key regulators of neuronal survival and repair during development but most importantly during adulthood and aging
The synthesis of ENT-A013 is reported in Scheme 1 and involves eight high-yielding steps from dehydroepiandrosterone (DHEA)
With triethyl phosphonoacetate in the presence of sodium ethoxide (EtONa) afforded the (E)-a,b-unsaturated ester 1 in 96% yield, which was reacted with tert-butyldimethylsilyl chloride (TBDMS-Cl) to afford the TBDMS-protected alcohol 2 in 93% yield
Summary
Endogenous neurotrophic factors constitute key regulators of neuronal survival and repair during development but most importantly during adulthood and aging. Growth Factor (NGF) was the first neurotrophin discovered and its activity is crucial for neuronal development, growth and survival, as well as synaptic functioning in the adult brain. It is well accepted that the elevated levels of misprocessed Aβ oligomers, which form the Aβ plaques, are the initiating step in the AD pathology [4]. This elevation is partly responsible for increased astrogliosis, decreased neurogenic potential, impaired synaptic functioning and, neuronal death. NGF signaling is critical for the survival and proper functioning of these affected neurons, while its depletion in a mouse model resulted in AD-like pathology, including Aβ plaques formation, tau hyperphosphorylation and synaptic dysfunction [9]. NGF treatment has been shown to ameliorate the Aβ-induced phenotype, preventing memory impairment [10]
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