SODYUM GLUKOZ KOTRANSPORTER-2 İNHİBİTÖRLERİNİN ALZHEİMER HASTALIĞI BENZERİ MODELDE NLRP3 İNFLAMAZOMU ARACILI NÖROİNFLAMASYON ÜZERİNE ETKİSİ

Abstract

Neuroinflammation, particularly microglial activation and NLRP3 inflammasome-mediated inflammatory responses, is an important component of Alzheimer’s disease (AD) pathogenesis. In addition to their glucose-lowering effects, sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to exert anti-inflammatory effects, which may be partly associated with suppression of the NLRP3 inflammasome. However, the effects of SGLT-2 inhibitors on NLRP3 inflammasome-related inflammatory responses under AD-like conditions have not yet been fully elucidated. In this study, the effects of bexagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and canagliflozin were evaluated in amyloid beta (Aβ)- and lipopolysaccharide (LPS)-induced BV2 microglial inflammation models using MTT, Griess, Western blot, and ELISA assays. In the Aβ model, bexagliflozin significantly reduced NLRP3, ASC, and caspase-1 protein levels as well as IL-1β and IL-18 levels, whereas dapagliflozin reduced NLRP3 and ASC protein levels and both cytokines. Ertugliflozin and canagliflozin showed more selective effects, while empagliflozin did not produce significant changes in the evaluated markers. In the LPS model, all five inhibitors significantly reduced NLRP3, ASC, IL-1β, and IL-18 levels, whereas caspase-1 was reduced only by bexagliflozin and empagliflozin. These findings support the further evaluation, particularly of bexagliflozin and dapagliflozin, in mechanistic and preclinical studies as potential pharmacological candidates targeting the NLRP3 axis in AH-associated neuroinflammation.