Lipopolysaccharide Induces Gliotoxicity in Hippocampal Astrocytes from Aged Rats: Insights About the Glioprotective Roles of Resveratrol

Astrocytes may undergo a functional remodeling with aging, acquiring a pro-inflammatory state. In line with this, resveratrol represents an interesting strategy for a healthier brain aging since it can improve glial functions. In the present study, we investigated the glioprotective role of resveratrol against lipopolysaccharide (LPS)-induced gliotoxicity in hippocampal aged astrocytes. Astrocyte cultures were obtained from aged rats (365 days old) and challenged in vitro with LPS in the presence of resveratrol. Cultured astrocytes from newborn rats were used as an age comparative for evaluating LPS gliotoxicity. In addition, aged rats were submitted to an acute systemic inflammation with LPS. Hippocampal astrocyte cultures were also obtained from these LPS-stimulated aged animals to further investigate the glioprotective effects of resveratrol in vitro. Overall, our results show that LPS induced a higher inflammatory response in aged astrocytes, compared to newborn astrocytes. Several inflammatory and gene expression alterations promoted by LPS in aged astrocyte cultures were similar in hippocampal tissue from aged animals submitted to in vivo LPS injection, corroborating our in vitro findings. Resveratrol, in turn, presented anti-inflammatory effects in aged astrocyte cultures, which were associated with downregulation of p21 and pro-inflammatory cytokines, Toll-like receptors (TLRs), and nuclear factor κB (NFκB). Resveratrol also improved astroglial functions. Upregulation of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) represent potential molecular mechanisms associated with resveratrol-mediated glioprotection. In summary, our data show that resveratrol can prime aged astrocytes against gliotoxic stimuli, contributing to a healthier brain aging.