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Neuropharmacology. 2016 Dec;111:266-282. doi: 10.1016/j.neuropharm.2016.09.007. Epub 2016 Sep 9.

Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation.

Author information

1
Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Greece; Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas (IMBB-FORTH), Heraklion, Greece.
2
Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.
3
Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, Salamanca, Spain.
4
Department of Internal Medicine III, Technical University Dresden, Dresden, Germany.
5
Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas (IMBB-FORTH), Heraklion, Greece.
6
Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece.
7
Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Greece. Electronic address: charalampn@uoc.gr.
8
Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Greece; Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas (IMBB-FORTH), Heraklion, Greece. Electronic address: gravania@uoc.gr.

Abstract

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.

KEYWORDS:

Molecular modeling; Nerve growth factor (NGF); Neurodegeneration; Neuronal apoptosis; Neurotrophin receptors signaling; Neurotrophins; STD NMR; Steroid; TrkA

[Indexed for MEDLINE]

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