Comparative Effects of Quercetin and its α- and β-D-glucoside Derivatives in LPS-Stimulated C6 Astroglial Cells

Neuroinflammation is a response of the central nervous system to injury, infection, or disease, involving the activation of glial cells and the release of cytokines and reactive species. When sustained or dysregulated, it contributes to the progression of neurological disorders. Quercetin (Que) is one of the most extensively studied flavonoids; however, its therapeutic application is limited by low bioavailability. Glucosylation has therefore emerged as a strategy to improve the physicochemical and biological properties of flavonoids. Previously, we synthesized the derivative quercetin-3'-α-D-glucoside (Que-3α) and characterized its pharmacokinetic profile and in vitro cytotoxicity. Here, we investigated the anti-inflammatory and antioxidant effects of Que and its derivatives, including the recently synthesized Que-3α and the naturally occurring β-glucoside, quercetin-3-β-D-glucoside (Que-3β), in a lipopolysaccharide (LPS)-induced inflammation model using C6 astroglial cells. Cells were pretreated for 2 h with the compounds (15 and 30 µM) and then stimulated with LPS (10 µg/mL) for 24 h. The compounds preserved mitochondrial activity, while Que and Que-3α reduced LPS-induced reactive oxygen species production, increased cell viability, and decreased apoptosis and necrosis. Notably, the Que-3α reduced iNOS expression, indicating more effective modulation of inflammatory mediators compared with the aglycone. These findings reinforce the biological properties of Que and suggest that α-glucosylation preserves the beneficial actions of Que while enhancing pharmacodynamic features relevant to neuroinflammation.