[CHIR99021 alleviates neuroinflammation in a mouse model of Parkinson's disease by inhibiting the GSK-3β/NF-κB pathway].

Abstract

Objectives: To investigate the effect of CHIR99021 for improving neuroinflammation in a mouse model of Parkinson's disease (PD) and the role of the GSK-3β/NF-κB pathway in mediating this effect.

Methods: In the cell experiment, induced SH-SY5Y cells were pretreated with 3 μmol/L CHIR99021 for 2 h prior to MPP+ treatment. In a male C57BL/6 mouse model of MPTP-induced PD, the effect of intraperitoneal injection of CHIR99021 for 7 days on motor function of the mice were assessed using behavioral tests. Western blotting and immunofluorescence staining were used to detect the changes in the GSK-3β/NF-κB pathway, NLRP3 inflammasome and autophagy in both SH-SY5Y cells and the mouse models.

Results: MPP+-treated SH-SY5Y cells showed significantly downregulated expression of p-GSK-3β protein and upregulated expressions of p-NF-κB p65, ASC, NLPR3, and caspase-1, and these changes were obviously attenuated by pretreatment with CHIR99021. Compared with normal mice, the PD mouse models showed significantly decreased motor function and reduced TH neurons in the brain with lowered expression of p-GSK-3β, increased expression of p-NF-κB p65 (Ser536), and upregulated ASC, NLPR3, and caspase-1 expressions. Treatment with CHIR99021 significantly increased the expression of p-GSK-3β, and reduced the expression of p-NF‑κB p65 (Ser536), ASC, NLPR3, and caspase-1.

Conclusions: CHIR99021 inhibits the GSK-3β/NF‑κB signaling pathway to improve motor function of PD mice, reduce neuroinflammation, and activate autophagy to maintain the homeostasis of intracellular environment, suggesting that targeting GSK-3β, a potential multifunctional therapeutic target, can simultaneously regulate multiple key pathological links in PD.