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

Abstract

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.

3-iodothyronamine inhibits apoptosis induced by myocardial ischemia reperfusion via the Akt/FoxO1 signaling pathway

“…In our previous research, inhibition of FoxO1 and PPARα disrupted cell metabolism, resulting in cardiomyocyte apoptosis (15). T1AM is a promising compound that regulates cellular metabolic reprogramming (26). Here, we demonstrated that T1AM significantly reduced the expression of Glut1, pFoxO1, and Akt, but increased the expression of FoxO1 and PPARα expression, which may represent a potential mechanism of suppression of cell apoptosis.…”

Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer’s Disease

“…Additionally, we showed the ability of SG2 to modulate lipid metabolism through the modulation of the AMPK/ACC pathway [22]. More recently, the protective effect of SG2 against neuronal plasticity impairment has been further confirmed in ex-vivo models of AD using mhAPP mice [23], suggesting that SG2 may have therapeutic potential in the treatment of AD.…”

“…A small panel of assays such as phosphodiesterase (PDE), histone deacetylases (HDACs) and specific kinases, especially those involved in cell cycle regulation, could be used to profile compounds in order to reduce the costs and time when ranking compounds at an early stage. Contextually, it has been recently showed that SG2 effects could be mediated by the activation of HDAC or sirtuin enzymes and specifically, SIRT4 and SIRT6 [23]; evaluating activity of new compounds against other epigenetic enzymes could be relevant in off-target liability profiling. We selected epigenetic modulators (HDAC4, HDAC6, HDAC8, HDAC9, SIRT7) and specific kinases (Aurora B, PDE4C1) to identify off-target effects linked to SG2 [43].…”

Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study

“…As extensively described in recent literature [ 10 , 41 ] for 3-iodothyronamine (T1AM), the lead compound of this class, cryogenic, cardiac and metabolic properties have been demonstrated in several animal models. Notably, T1AM and derivatives have also shown great application potential as novel pleiotropic drugs for the treatment of dementia and NDDs [ 6 , 42 ]. However, one of the limiting factors in the treatment of NDDs is represented by the presence of the blood brain barrier (BBB), a complex structure that behaves like a physical barrier, protecting the brain from infections, neurotoxins and maintaining the balance of nutrients and macromolecules between the brain and the external environment, which in turn can halt the delivery of drugs to the brain [ 43 ].…”