Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ <sub>1–42</sub> -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease
Mehdi Alami, Echarki Zerif, Abdelouahed Khalil, Nabil Hajji, Charles Ramassamy, Guy Lacombe, Benoît Laurent, Alan A. Cohen, Jacek M. Witkowski, Denis Gris, Ton Bunt, Olaf van Tellingen, Katsuiku Hirokawa, Tamàs Fülöp, Hicham Berrougui
Abstract
Background Alzheimer's disease (AD) is a chronic brain degenerative disease that leads to dementia. Objective The aim of the present study is to investigate the neuroprotective impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) (empagliflozin and dapagliflozin) on tau phosphorylation, oxidative stress, and neuroinflammation. Methods We used MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, annexin-V-FITC kit, and DCFH-DA (dichloro-dihydro-fluorescein diacetate) to respectively evaluate the effect of the SGLT2i (empagliflozin and dapagliflozin) on amyloid-β (Aβ) 1–42 -induced neuronal death, apoptosis, and oxidative stress. The expression of NLRP3-inflammasome, phospho-Tau181, glycogen synthase kinase-3 beta (GSK-3β), cyclin-dependent kinase 5 (CdK5), and histone deacetylase 6 (HDAC6), was quantified by flow cytometry. Drug distribution in the mice's brains was assessed by liquid chromatography-mass spectrometry (LC-MS). Results Aβ 1–42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins. SGLT2i significantly reduced Aβ 1–42 -induced reactive oxygen species generation, downregulated NLRP3-inflammasome, and diminished tau pathology. Mechanistically, the last effect involved the modulation of GSK-3β and CdK5 protein expression. However, the tested treatments did not modify the Aβ 1–42 -stimulating effect of HDAC6. Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution. Conclusions SGLT2i empagliflozin and dapagliflozin exhibited neuroprotective actions against human Aβ 1–42 -induced neurotoxicity.