Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ 1–42 -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease
Restricted accessResearch articleFirst published online May, 2025
Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ 1–42 -induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease
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
Aβ1–42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins. SGLT2i significantly reduced Aβ1–42-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 Aβ1–42-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 Aβ1–42-induced neurotoxicity.
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