RT Journal Article
T1 Gracilin A Derivatives Target Early Events in Alzheimer’s Disease: inVitro Effects on Neuroinflammation and Oxidative Stress
A1 Alvariño Romero, Rebeca
A1 Alonso López, Eva
A1 Abbasov, Mikail E.
A1 Chaheine, Christian M.
A1 Conner, Michael L.
A1 Romo, Daniel
A1 Alfonso Rancaño, María Amparo
A1 Botana López, Luis Miguel
K1 Gracilin
K1 Neuroinflammation
K1 Antioxidant
K1 Alzheimer’s disease
K1 Nrf2
K1 Neuroprotection
AB The search for compounds capable of targeting early pathological changes of Alzheimer̀s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis (PDR) strategy, and found to possess potent neuroprotective effects. In this work, the previously described derivatives 1–7 which demonstrated mitochondrial-mediated, antioxidant effects were chosen for further study. The ability of compounds to modulate the expression of antioxidant genes (CAT, GPx, SODs, and Nrf2) was determined in SH-SY5Y cells, and the simplified derivatives 2 and 3 were found to be the most effective. The anti-neuroinflammatory properties of all derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Several derivatives decreased the release of cytokines (Il-1β, IL-6, GM-CSF, and TNF-α) and other damaging molecules (ROS, NO) and also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well coculture with BV2 and SH-SY5Y cells and several derivatives increased SH-SY5Y survival. This present work demonstrates the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives 2 and 3 showed the greatest potential as lead compounds for further development
PB American Chemical Society
YR 2019
FD 2019
LK http://hdl.handle.net/10347/31639
UL http://hdl.handle.net/10347/31639
LA eng
NO Alvariño, R., Alonso, E., Abbasov, M.E., Chaheine, C.M., Conner, M.L., Romo, D., Alfonso, A., Botana, L.M. (2019). Gracilin A Derivatives Target Early Events in Alzheimer’s Disease: in Vitro Effects on Neuroinflammation and Oxidative Stress. ACS Chemical Neuroscience,10 (9), 4102-4111
NO The research leading to these results has received funding fromthe following FEDER cofunded-grants. From Consellería de Cultura, Educación e Ordenación Universitaria Xunta de Galicia, 2017 GRC GI-1682 (ED431C 2017/01). From CDTI and Technological Funds, supported by Ministerio de Economía, Industria y Competitividad, AGL2014-58210-R, AGL2016-78728-R (AEI/FEDER, UE), ISCIII/PI16/01830 and RTC-2016-5507-2, ITC-20161072. From European Union POCTEP 0161-Nanoeaters−1-E-1, Interreg AlertoxNet EAPA-317-2016, Interreg Agritox EAPA-998-2018 and H2020 778069-EMERTOX. Support from NIH (R37GM052964 to D.R.) and the Robert A. Welch Foundation (AA-1280 to D.R.) is also gratefully acknowledged.
NO This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical neuroscience, copyright © 2019 American Chemical Society, after peer review and technical editing by the publisher.
DS Minerva
RD 28 abr 2026