Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation.
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.
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.
Iosif
I
Pediaditakis
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.
Paschalis
P
Efstathopoulos
Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Kyriakos C
KC
Prousis
Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Maria
M
Zervou
Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, Salamanca, Spain.
Juan Carlos
JC
Arévalo
Department of Internal Medicine III, Technical University Dresden, Dresden, Germany.
Vasileia I
VI
Alexaki
Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas (IMBB-FORTH), Heraklion, Greece.
Vassiliki
V
Nikoletopoulou
Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece.
Efthymia
E
Karagianni
Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Constantinos
C
Potamitis
Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas (IMBB-FORTH), Heraklion, Greece.
Nektarios
N
Tavernarakis
Department of Internal Medicine III, Technical University Dresden, Dresden, Germany.
Triantafyllos
T
Chavakis
Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece.
Andrew N
AN
Margioris
Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece.
Maria
M
Venihaki
Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Theodora
T
Calogeropoulou
Department of Pharmacology, School of Medicine, University of Crete, Heraklion, Greece. Electronic address: charalampn@uoc.gr.
Ioannis
I
Charalampopoulos
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.
Achille
A
Gravanis
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D003412:Cricetulus; D003687:Dehydroepiandrosterone / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D020932:Nerve Growth Factor / Q000235:genetics / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D020917:Receptor, trkA / Q000819:agonists / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
C000618344:BNN27 compound; D011994:Recombinant Proteins; D003687:Dehydroepiandrosterone; D020932:Nerve Growth Factor; D020917:Receptor, trkA
Molecular modeling; Nerve growth factor (NGF); Neurodegeneration; Neuronal apoptosis; Neurotrophin receptors signaling; Neurotrophins; STD NMR; Steroid; TrkA