Ellagic acid regulates astrocytic responses under inflammatory conditions in primary astrocyte cultures: effects on oxidative stress, inflammatory cytokines, and glycogen synthase kinase-3β

BACKGROUND: Neuroinflammation involves the activation of glial cells, particularly astrocytes, and microglia, in response to pathological stimuli. Astrocyte activation is characterized by increased pro-inflammatory cytokines and oxidative stress. Given their role in neuroinflammation, targeting astrocytic mechanisms presents potential therapeutic opportunities. Ellagic acid (EA), a phenolic compound, exhibits antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated the effect of EA on astrocytes from neonatal rats exposed to lipopolysaccharide (LPS), a potent proinflammatory agent widely used to induce neuroinflammation in vitro. METHODS AND RESULTS: Astrocytes were pretreated with EA (50, 100, and 200 µM) for 48 h and subsequently exposed to LPS (1 µg/mL) for 3h. Cell viability and proliferation, inflammatory and oxidative stress parameters were evaluated. LPS decreased astrocytic viability and increased cell proliferation and EA prevented these alterations. EA also attenuated the LPS-induced increase in reactive oxygen species and nitrite levels and the decrease in sulfhydryl content and antioxidant enzyme activities. LPS induced an increase in gene expression of interleukin 1β and tumor necrosis factor-alpha, and EA treatment attenuated these alterations. Conversely, EA increased interleukin 6 (IL-6) and glycogen synthase kinase-3 beta mRNA expression compared with LPS-only exposure. LPS increased IL-6 levels and decreased interleukin 10 (IL-10) levels in astrocytes, and EA at 100 µM prevented the reduction in IL-10 levels but did not significantly modify IL-6 levels compared with LPS group. CONCLUSION: EA modulates oxidative and inflammatory markers in LPS-stimulated astrocytes. Further studies are needed to clarify the underlying mechanisms and evaluate these effects in more complex models of neuroinflammation.