Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer's Disease.
Santorelli, Filippo M
Wakelam, Michale OJ
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Runfola, M., Perni, M., Yang, X., Marchese, M., Bacci, A., Mero, S., Santorelli, F. M., et al. (2021). Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer's Disease.. Pharmaceuticals (Basel), 14 (12) https://doi.org/10.3390/ph14121330
The identification of effective pharmacological tools for Alzheimer's disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming. We demonstrate herein that SG2 acts in a pleiotropic manner to induce recovery in a C. elegans model of AD based on the overexpression of Aβ42 and improves learning abilities in the 5XFAD mouse model of AD. Further, in vitro ADME-Tox profiling and toxicological studies in zebrafish confirmed the low toxicity of this compound, which represents a chemical starting point for AD drug development.
Alzheimer’s disease, polypharmacology, C. elegans, autophagy, drug discovery, zebrafish, 5XFAD mice
Regione toscana (DEM-AGING)
Telethon Grant Projects (GGP20011)
MIUR (Dipartimenti di eccellenza 2018-2022)
External DOI: https://doi.org/10.3390/ph14121330
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332059