Journal
NEUROPHARMACOLOGY
Volume 111, Issue -, Pages 266-282Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2016.09.007
Keywords
Neurotrophins; Nerve growth factor (NGF); TrkA; Neurodegeneration; Neurotrophin receptors signaling; Neuronal apoptosis; Steroid; STD NMR; Molecular modeling
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Funding
- ERC01 National Initiative grant, General Secretariat for Research Technology - Bionature E.A. Ltd
- Bodossaki Foundation
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Nerve growth factor (NGF) holds a pivotal role in brain development and maintenance, been also involved in the pathophysiology of neurodegenerative diseases. Here, we provide evidence that a novel C17-spiroepoxy steroid derivative, BNN27, specifically interacts with and activates the TrkA receptor of NGF, inducing phosphorylation of TrkA tyrosine residues and down-stream neuronal survival-related kinase signaling. Additionally, BNN27 potentiates the efficacy of low levels of NGF, by facilitating its binding to the TrkA receptors and differentially inducing fast return of internalized TrkA receptors into neuronal cell membranes. Furthermore, BNN27 synergizes with NGF in promoting axonal outgrowth, effectively rescues from apoptosis NGF-dependent and TrkA positive sympathetic and sensory neurons, in vitro, ex vivo and in vivo in NGF null mice. Interestingly, BNN27 does not possess the hyperalgesic properties of NGF. BNN27 represents a lead molecule for the development of neuroprotective TrkA receptor agonists, with potential therapeutic applications in neurodegenerative diseases and in brain trauma. (C) 2016 Elsevier Ltd. All rights reserved.
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