Febuxostat Inhibits MPP+-Induced Inflammatory Response Through Inhibiting the JNK/NF-κB Pathway in Astrocytes.

Abstract

Parkinson's disease (PD) is a severe neurodegenerative disease lacking effective clinical therapies. It is reported that astrocyte-associated neuroinflammation and oxidative stress are involved in the pathological mechanism of PD. In the present study, we aimed to investigate the protective effect of febuxostat against 1 methyl 4 phenyl pyridine (MPP+)-induced injury on primary astrocytes to highlight the potential therapeutic property of febuxostat in PD.MPP+ was used to induce an in vitro PD model in primary rat astrocytes. The levels of ROS and intracellularly reduced GSH were determined using DCFH-DA assay and a commercial GSH kit, respectively. MTT and LDH release assays were utilized to evaluate the cell viability of astrocytes. The expressions of IL-8, IL-1β, TNF-α, MMP-2, and MMP-9 in the astrocytes were detected using qRT-PCR and ELISA assays. QRT-PCR and Western blot analysis were used to determine the expression levels of GFAP in astrocytes. The expression of p-JNK and nuclear levels of NF-κB p65 were evaluated using Western blot analysis. The transcriptional activity of NF-κB was measured using the luciferase activity assay.Firstly, the elevated levels of ROS and decreased levels of intracellularly reduced GSH in primary astrocytes induced by MPP+ were significantly ameliorated by febuxostat. Secondly, treatment with febuxostat rescued MPP+-induced reduction in cell viability and increased LDH release. Thirdly, febuxostat alleviated MPP+-induced inflammatory responses in astrocytes by reducing the expressions of IL-8, IL-1β, TNF-α, GFAP, MMP-2, and MMP-9. Importantly, we found that febuxostat mitigated activation of the JNK/NF-κB signaling pathway by inhibiting the phosphorylation of JNK and nuclear translocation of NF-κB p65.Febuxostat attenuated MPP+-induced inflammatory response by suppressing the JNK/NF-κB signaling pathway in astrocytes.