Empagliflozin and dapagliflozin, sodium glucose cotransporter 2 inhibitors, may improve cognitive dysfunctions: in silico and in vivo findings.

Abstract

Type 2 Diabetes Mellitus (T2D) accelerates cognitive decline through a complex interaction of metabolic, oxidative, inflammatory, and vascular pathways and is widely recognized as a significant risk factor for Alzheimer's disease (AD). Sodium-glucose cotransporter (SGLT)2 inhibitors are widely used in the treatment of T2D, and accumulating evidence suggests that they may influence neurodegenerative processes beyond their glycemic effects. In this context, the present study investigated the potential contributions of empagliflozin (EMPA) and dapagliflozin (DAPA) to cognitive function by evaluating their in silico interactions with targets associated with oxidative stress, inflammation, and neuroprotection, including SGLT1, SGLT2, acetylcholinesterase (AChE), superoxide dismutase (SOD), receptor for advance glycation end-products (RAGE), and interleukin (IL)-1β. Furthermore, cognitive impairments in streptozotocin/nicotinamide-induced T2D were investigated in vivo by behavioral tests in rats. Biochemical alterations in brain tissues were evaluated using ELISA measurements, which encompassed the levels of SOD, RAGE, and IL-1β. Hematoxylin and eosin (H&E) staining was used to evaluate the structure of hippocampal and cortical tissue for histological assessment. Molecular docking analyses indicated that EMPA showed notably stronger interactions with AD-relevant targets such as SGLT1/2 and AChE than DAPA. Both EMPA and DAPA elevated SOD levels in brain tissue. Consistent with these biochemical improvements, behavioral assessments demonstrated enhanced learning and memory performance in treated rats relative to the T2D group. Nonetheless, histological analyses revealed that both drugs produced improvements in the cortex and hippocampus. In conclusion, EMPA and DAPA may modulate T2D-associated AD through multiple metabolic pathways, and further investigation is warranted to elucidate their contributions.