Resveratrol Mitigates High Glucose-Induced Inflammation in Astroglial Cells

<b>Background/Objectives:</b> Changes in glucose metabolism impact central nervous system (CNS) homeostasis and, consequently, can lead to cognitive impairment and an increased risk for neurodegenerative and neuropsychiatric disorders. Astrocytes are glial cells that act as key regulators of brain glucose metabolism, thus representing important cellular targets for studies of different pathophysiological conditions, including hyperglycemia. Resveratrol, a natural polyphenol, has emerged as a potential protective strategy against diabetes and its complications; however, its glioprotective effects remain unclear. Based on these observations, we evaluated whether resveratrol could modify the inflammatory response in astroglial cells exposed to experimental hyperglycemic conditions. <b>Methods:</b> After reaching confluence, C6 astroglial cells were pre-incubated with 10 µM resveratrol in serum-free DMEM with 6 mM glucose for 24 h. The medium was then replaced with serum-free DMEM containing 12 mM glucose and 10 µM resveratrol for another 24 h. Controls were maintained in 6 mM glucose. Analyses included cell viability, metabolic activity, glucose and glutamate uptake, cytokine quantification by ELISA, and gene expression by RT-qPCR. <b>Results:</b> We show that high glucose levels modulate glucose and glutamate metabolism, and increase neuroinflammation, through the modulation of inflammatory mediators. In addition, high glucose upregulated the gene expressions of inducible nitric oxide synthase (iNOS), nuclear factor κB (NFκB), cyclooxygenase 2 (COX2), and Toll-like receptor 4 (TLR4) while decreasing mRNA levels of NLR family pyrin domain containing 3 (NLRP3) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). However, resveratrol was able to prevent most of these effects, particularly the high glucose-triggered inflammatory response. Resveratrol also modulated heme oxygenase 1 (HO-1) and nuclear factor erythroid-derived 2-like 2 (Nrf2), important targets associated with cellular protection. <b>Conclusions:</b> Our findings reinforce resveratrol as a potential glioprotective strategy against diabetes-related brain toxicity.