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Identifier	000393074
Title	The neurotrophic effects of endogenous and synthetic neurosteroids : structure-function analysis of their interactions with neurotrophin receptors and their biological role in neuroprotection
Alternative Title	Οι νευροτροφικές δράσεις ενδογενών και συνθετικών νευροστεροειδών
Author	Πεδιαδιτάκης, Ιωσήφ
Thesis advisor	Γραβάνης, Αχιλλέας
Reviewer	Ταβερναράκης, Νεκτάριος Χαραλαμπόπουλος, Ιωάννης Μαργιωρής, Ανδρέας Καστανάς, Ηλίας Θερμού, Κυριακή Ηλιόπουλος, Ιωάννης
Abstract	Neuronal cell fate is majorly governed by the actions of growth factors, such as neurotrophins. These specific ligands and their receptors activity are regulated by multiple cellular parameters. Indeed, we have recently shown that neurosteroid dehydroepiandrosterone (DHEA) prevents neuronal apoptosis through binding to NGF receptors, namely TrkA and p75NTR. In this study we provide evidence that DHEA interacts with the other two mammalian neurotrophin receptors, i.e., the TrkB and TrkC, as well as their invertebrate counterparts (orthologs) in mollusks Lymnaea and Aplysia, and in cephalochordate fish Amphioxus, supporting the hypothesis that during evolution DHEA may have served as a primordial neurotrophic factor, promoting neuronal survival in species with less complex nervous systems. A large number of experimental and clinical studies suggest that endogenous neurotrophins are involved in the pathopysiology of many neurodegenerative diseases. However, despite their demonstrated beneficial effects on neuronal survival and protection, the therapeutic usefulness of neurotrophins is compromised by their polypeptide nature and their restricted penetrance to the blood-brain barrier (BBB). To overcome this limitation, small molecules –like DHEA- which could mimic the effects of neurotrophic factors would be therapeutically ideal. However, DHEA is metabolized in vivo to sex steroids, affecting the endocrine system. We have recently synthesized 17-spiro analogs of DHEA with anti-apoptotic, neuroprotective properties (IC50 at nanomolar levels), deprived of androgenic-estrogenic actions. In the present study, we report that synthetic DHEA derivative, BNN27, specifically interacts with both NGF receptors, TrkA and p75NTR, at nanomolar concentrations. BNN27 induces TrkA tyrosine phosphorylation, affecting downstream signaling of Akt and MAPKs in sympathetic neurons and regulates TrkA internalization, however in a different time pattern than that of NGF. Moreover, BNN27 was shown to promote the interaction of p75NTR receptors with its effector factors RhoGDI, RIP2 and TRAF6. It also significantly reverses apoptosis of NGF-dependent embryonic sensory neurons of NGF null mice. BNN27 itself was not effective in to mimicking NGF in the induction of neurite elongation, perhaps due to its differential endosome’s turn over. However, combination of BNN27 with NGF results in enhancement of neurites’ length. BNN27 may serve as a lead molecule to develop BBB permeable, neurotrophin-like small molecules (microneurotrophins) with potential applications in the treatment of neurodegenerative diseases and brain disorders.
Language	English
Issue date	2015-03-31
Collection	School/Department--School of Medicine--Department of Medicine--Doctoral theses
	Type of Work--Doctoral theses
Permanent Link	https://elocus.lib.uoc.gr//dlib/7/9/5/metadata-dlib-1431598429-147986-14850.tkl
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