title: BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis.
abstract: Neurotrophin receptors mediate a plethora of signals affecting neuronal survival. The p75 pan-neurotrophin receptor controls neuronal cell fate after its selective activation by immature and mature isoforms of all neurotrophins. It also exerts pleiotropic effects interacting with a variety of ligands in different neuronal or non-neuronal cells. In the present study, we explored the biophysical and functional interactions of a blood-brain-barrier (BBB) permeable, C17-spiroepoxy steroid derivative, BNN27, with p75NTRreceptor. BNN27 was recently shown to bind to NGF high-affinity receptor, TrkA. We now tested the p75NTR-mediated effects of BNN27 in mouse Cerebellar Granule Neurons (CGNs), expressing p75NTR, but not TrkA receptors. Our findings show that BNN27 physically interacts with p75NTRreceptors in specific amino-residues of its extracellular domain, inducing the recruitment of p75NTRreceptor to its effector protein RIP2 and the simultaneous release of RhoGDI in primary neuronal cells. Activation of the p75NTRreceptor by BNN27 reverses serum deprivation-induced apoptosis of CGNs resulting in the decrease of the phosphorylation of pro-apoptotic JNK kinase and of the cleavage of Caspase-3, effects completely abolished in CGNs, isolated from p75NTRnull mice. In conclusion, BNN27 represents a lead molecule for the development of novel p75NTRligands, controlling specific p75NTR-mediated signaling of neuronal cell fate, with potential applications in therapeutics of neurodegenerative diseases and brain trauma.
authors.affiliation: Department of Pharmacology, School of Medicine, University of CreteHeraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-HellasHeraklion, Greece.
authors.forename: Iosif
authors.initials: I
authors.lastname: Pediaditakis
authors.affiliation: Department of Pharmacology, School of Medicine, University of CreteHeraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-HellasHeraklion, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kourgiantaki
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation Athens, Greece.
authors.forename: Kyriakos C
authors.initials: KC
authors.lastname: Prousis
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation Athens, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Potamitis
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation Athens, Greece.
authors.forename: Kleanthis P
authors.initials: KP
authors.lastname: Xanthopoulos
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Zervou
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation Athens, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.affiliation: Department of Pharmacology, School of Medicine, University of Crete Heraklion, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Charalampopoulos
authors.affiliation: Department of Pharmacology, School of Medicine, University of CreteHeraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-HellasHeraklion, Greece.
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
keywords: DHEA; STD NMR; molecular dynamics; nerve growth factor (NGF); neuronal apoptosis; neurotrophin receptors signaling; p75 neurotrophin receptor; steroid