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Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6

1
Laboratory of Biochemistry, Department of Pathology, University of Pisa, 56100 Pisa, Italy
2
Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
3
Department of Clinical and Experimental Medicine, University of Pisa, 56100 Pisa, Italy
4
Sant’Anna School of Advanced Studies, 56127 Pisa, Italy
5
Unit of Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
6
IRCCS Neuromed, 86077 Pozzilli (IS), Italy
7
Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, 56126 Pisa, Italy
8
National Research Council (CNR), Institute of Neuroscience, 56124 Pisa, Italy
*
Author to whom correspondence should be addressed.
These authors have contributed equally to this work.
Molecules 2020, 25(5), 1054; https://doi.org/10.3390/molecules25051054
Received: 30 November 2019 / Revised: 12 February 2020 / Accepted: 25 February 2020 / Published: 26 February 2020
(This article belongs to the Section Medicinal Chemistry)
3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment. View Full-Text
Keywords: 3-iodothyronamine (T1AM); thyronamine-like analogs; multi-target directed ligand; neurodegeneration; Sirt6; autophagy; ubiquitine-proteasome; long term potentiation (LTP); mhAPP mouse model 3-iodothyronamine (T1AM); thyronamine-like analogs; multi-target directed ligand; neurodegeneration; Sirt6; autophagy; ubiquitine-proteasome; long term potentiation (LTP); mhAPP mouse model
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Bellusci, L.; Runfola, M.; Carnicelli, V.; Sestito, S.; Fulceri, F.; Santucci, F.; Lenzi, P.; Fornai, F.; Rapposelli, S.; Origlia, N.; Zucchi, R.; Chiellini, G. Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6. Molecules 2020, 25, 1054.

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