Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ _1–42 -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease

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.