Ser9p-GSK3β Modulation Contributes to the Protective Effects of Vitamin C in Neuroinflammation

• Published in: Nutrients 2024-04, Vol.16 (8), p.1121
• Main Authors: Ruggiero, Melania, Cianciulli, Antonia, Calvello, Rosa, Porro, Chiara, De Nuccio, Francesco, Kashyrina, Marianna, Miraglia, Alessandro, Lofrumento, Dario Domenico, Panaro, Maria Antonietta
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Antibodies; Aprotinin; Ascorbic Acid - pharmacology; Cell Line; Cells; Cytokines; Diagnostic reagents industry; Disease Models, Animal; Ethylenediaminetetraacetic acid; Genotype & phenotype; Glycogen; Glycogen Synthase Kinase 3 beta - metabolism; GSK3β; Kinases; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; microglia; Microglia - drug effects; Microglia - metabolism; neuroinflammation; Neuroinflammatory Diseases - drug therapy; neuroprotection; Neuroprotective Agents - pharmacology; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Pathogenesis; Phosphorylation - drug effects; Proteins; Scientific equipment and supplies industry; Serine - metabolism; Synthesis; Vitamin C; Wnt/β-catenin signaling pathway
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu16081121

The prolonged activation of microglia and excessive production of pro-inflammatory cytokines can lead to chronic neuroinflammation, which is an important pathological feature of Parkinson's disease (PD). We have previously reported the protective effect of Vitamin C (Vit C) on a mouse model of PD. However, its effect on microglial functions in neuroinflammation remains to be clarified. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase having a role in driving inflammatory responses, making GSK3β inhibitors a promising target for anti-inflammatory research. In this study, we investigated the possible involvement of GSK3β in Vit C neuroprotective effects by using a well-known 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and a cellular model of neuroinflammation, represented by Lipopolysaccharide (LPS)-activated BV-2 microglial cells. We demonstrated the ability of Vit C to decrease the expression of different mediators involved in the inflammatory responses, such as TLR4, p-IKBα, and the phosphorylated forms of p38 and AKT. In addition, we demonstrated for the first time that Vit C promotes the GSK3β inhibition by stimulating its phosphorylation at Ser9. This study evidenced that Vit C exerts an anti-inflammatory function in microglia, promoting the upregulation of the M2 phenotype through the activation of the Wnt/β-catenin signaling pathway.