Alzheimer’s disease (AD) is the most common neurodegenerative disorder. AD and dementia associated with several fatal clinical disorders is a considerable social, economic, and medical challenge. Neuroinflammation is a key factor of Alzheimer’s disease (AD) and other neurodegeneration conditions. It has been reported that glycogen synthase kinase-3β (GSK-3β) mediates the release of proinflammatory cytokines and promotes inflammatory responses in peripheral immune cells. Microglia are the resident mononuclear immune cells of the central nervous system (CNS). Here we investigated the anti-neuroinflammatory effects of a semisynthetic flavonoid GSK-3β inhibitor [(2S,3S,4R,5R,6S)-6-(2-(3,4-dimethoxyphenyl)-5,7-dimethoxy-4-oxo-4H-chromen-6-yl)-3,4,5-trihydroxy-N-((S)-1,1,1-trifluoropropan-2-yl)tetrahydro-2H-pyran-2-carboxamide; TFGF-18] in lipopolysaccharide (LPS) activated SIM-A9 microglial cells. The results showed TFGF-18 significantly inhibited LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-α and IL-1β. The migration of activated SIM-A9 cells was also greatly reduced with pretreatment of TFGF-18 in a scratch assay. Analyses in signaling pathways demonstrated that TFGF-18 led to the suppression of LPS-induced GSK-3β activation and p65/NF-κB activity. Furthermore, the co-culture of SIM-A9 with SH-SY5Y neuroblastoma cells showed that TFGF-18 suppressed the microglia-mediated neurotoxicity <i>in vitro</i>. Taken together, TFGF-18 inhibits LPS-stimulated microglia activation through collective regulation of GSK-3β and p65/NF-κB signaling. The results indicate a potential role of TFGF-18 in neuroprotection via its anti-neuroinflammatory effect. Therefore, modulation of microglia responses may provide a therapeutic target for the treatment of AD and other neurodegeneration conditions.

Anti-neuroinflammatory effects of GSK-3β inhibitor TFGF-18 in LPS-activated SIM-A9 microglial cells

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.