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Published on: September 2, 2010
Ser9p-GSK3β Modulation Contributes to the Protective Effects of Vitamin C in Neuroinflammation
Melania Ruggiero1, Antonia Cianciulli1, Rosa Calvello1
1Department of Biosciences, Biotechnologies and Environment, University of Bari, 70125 Bari, Italy.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Vitamin C (Vit C) reduces neuroinflammation in Parkinson's disease (PD) models by inhibiting microglial activation. It achieves this by targeting Glycogen synthase kinase 3β (GSK3β), promoting an anti-inflammatory M2 phenotype.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Chronic neuroinflammation, driven by activated microglia and pro-inflammatory cytokines, is key in Parkinson's disease (PD).
- Vitamin C (Vit C) has shown protective effects in PD models, but its impact on microglial neuroinflammation needs clarification.
- Glycogen synthase kinase 3β (GSK3β) inhibitors are potential anti-inflammatory targets due to GSK3β's role in inflammatory responses.
Purpose of the Study:
- To investigate the role of GSK3β in Vitamin C's neuroprotective effects.
- To elucidate the anti-inflammatory mechanisms of Vit C in microglia.
Main Methods:
- Utilized a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD.
- Employed a cellular model using Lipopolysaccharide (LPS)-activated BV-2 microglial cells to study neuroinflammation.
Main Results:
- Vit C decreased inflammatory mediators like TLR4, p-IKBα, and phosphorylated p38 and AKT.
- Demonstrated that Vit C inhibits GSK3β by increasing its phosphorylation at Ser9.
- Showed Vit C's anti-inflammatory effect in microglia.
Conclusions:
- Vit C exerts anti-inflammatory effects on microglia.
- Vit C promotes the M2 microglial phenotype.
- This occurs via activation of the Wnt/β-catenin signaling pathway.
