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Identifier 000419775
Title Evaluation of nοvel microneurotrophin compounds on activating neurotrophin receptors
Alternative Title Αξιολόγηση της ενεργοποίησης υποδοχέων νευροτροφινών έπειτα από την επίδραση νέων συνθετικών μορίων μικρονευροτροφινών
Author Βουτυράκη Χρυσάνθη Ι.
Thesis advisor Γραβάνης, Αχιλλέας
Reviewer Χαραλαμπόπουλος, Ιωάννης
Τζαμαρίας, Δημήτρης
Abstract Neuronal cell survival and differentiation is determined by multiple events, one of which is the binding of neurotrophic factors to their respective high affinity receptors, leading to a cascade of molecular interactions. Neurotrophins and their receptors have been reported as deregulated in many neurodegenerative diseases, however due to their polypeptidic nature and their restricted penetration to the blood-brain barrier (BBB), their therapeutic application is compromised. Studies in our laboratory have proven that the neurosteroid dehydroepiandrosterone (DHEA) interacts with the nerve growth factor (NGF) receptors, namely TrkA and p75NTR, efficiently activating downstream signaling pathways and preventing neuronal apoptosis. Nevertheless, DHEA as a steroid hormone is metabolized in vivo to sex hormones; thus its pharmacological potential for neurodegenerative conditions is limited. Overcoming these limitations, small DHEA-like molecules deprived of androgenic-estrogenic actions and effectively mimicking the effects of neurotrophins have been recently synthesized and characterized. We have shown that BNN27, a synthetic DHEA derivative, interacts with TrkA and p75NTR receptors and activates downstream signaling pathways aiming to prevent neuronal apoptosis and promote neuroprotection in vitro and in vivo. The present study focuses on the characterization of newly synthesized, neurotrophin-like small molecules named as microneurotrophins. By utilizing receptor’s phosphorylation assays, we assessed the efficacy of each analog to activate TrkA receptor and by employing cell survival assays we investigated their anti-apoptotic properties. Our results indicate that compounds BNN397 and BNN403 efficiently activate the receptor in a 20-minute trial; BNN218, BNN219, BNN396 and BNN398 activate the receptor after 30 minutes while BNN218 and BNN398 have a greater impact on rescuing cells from apoptosis. The microneurotrophin analogs which stand out from both experiments are BNN218 and BNN398 and we propose that future work shall validate our results and further investigate their functional properties in vitro and in vivo. We hope that these new microneurotrophin compounds will exhibit good pharmacological properties and will qualify as therapeutic agents towards the treatment of neurodegenerative diseases.
Language English
Subject Alzheimer's disease
Issue date 2018-11-23
Collection   Faculty/Department--Faculty of Sciences and Engineering--Department of Biology--Post-graduate theses
  Type of Work--Post-graduate theses
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