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

NEUROPHARMACOLOGY

卷:111

Article

Pediaditakis, Iosif^1,2  Efstathopoulos, Paschalis^1,2  Prousis, Kyriakos C.³  Zervou, Maria³  Arevalo, Juan Carlos⁴  Alexaki, Vasileia I.⁵  Nikoletopoulou, Vassiliki²  Karagianni, Efthymia⁶  Potamitis, Constantinos³  Tavernarakis, Nektarios²  Chavakis, Triantafyllos⁵  Margioris, Andrew N.⁶  Venihaki, Maria⁶  Calogeropoulou, Theodora³  Charalampopoulos, Ioannis¹  Gravanis, Achille^1,2 

[1] Univ Crete, Sch Med, Dept Pharmacol, Iraklion, Greece

[2] Fdn Res & Technol Hellas IMBB FORTH, Inst Mol Biol & Biotechnol, Iraklion, Greece

[3] Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Athens, Greece

[4] Univ Salamanca, INCyL, Dept Cell Biol & Pathol, Salamanca, Spain

[5] Tech Univ Dresden, Dept Internal Med 3, Dresden, Germany

[6] Univ Crete, Sch Med, Dept Clin Chem, Iraklion, Greece

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

DOI  :  10.1016/j.neuropharm.2016.09.007

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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