Uric acid alleviates the inflammatory response in LPS-induced BV2 cells and MPTP-induced PD mice by resisting ferroptosis through the Nrf2 signalling pathway.
Zhou Dongmei, Xiong Tian, Yang Bing, Liu Fanjie, Mo Xianglai, Chen Ting, Lu Peipei, Liang Xinghuan, Li Li, Qin Yingfen, Lu Decheng, Huang Feng, Yang Xi
Abstract
BACKGROUND: Neuroinflammation, oxidative stress, and ferroptosis are implicated in Parkinson' s disease (PD) pathogenesis. Epidemiological studies suggest that elevated uric acid (UA) levels may reduce PD risk, but the precise molecular mechanisms involved remain unclear. In this study, we investigated the effects of UA in lipopolysaccharide (LPS) or MPP+-stimulated BV2 microglia and MPTP-induced PD mouse models. METHODS: BV2 cells are recognized as a standardized and reproducible neural inflammatory cell model for mechanism exploration. The anti-ferroptosis and anti-inflammatory effects of UA were assessed in LPS or MPP+ stimulated BV2 microglia and in an MPTP-induced PD mouse model. Western blot, qPCR, ELISA, and immunofluorescence were used to analyse the expression of inflammasome-related markers. ROS, MDA, GSH, and Fe²⁺ levels were measured using testing kits, while mitochondrial ultrastructure was evaluated through transmission electron microscopy. PD-related markers were assessed by ethology and immunohistochemistry. The Nrf2 inhibitor ML385 was employed to validate pathway specificity. RESULTS: We found that UA treatment reduced the expression of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), ROS production, lipid peroxidation, and intracellular Fe²⁺ in BV2 microglia while increasing the antioxidant capacity and preserving the mitochondrial ultrastructure. In MPTP-treated mice, UA improved motor performance, preserved dopaminergic neuron density in the substantia nigra, and reduced neuroinflammation. UA activated Nrf2 signalling and upregulated GPX4 expression, which were attenuated by ML385, confirming the Nrf2 dependence of these effects. CONCLUSION: UA alleviates ferroptosis and neuroinflammation in LPS or MPP+ stimulated BV2 microglia and MPTP-induced PD mouse models through the activation of the Nrf2 signalling pathway.
Key Findings
- Uric acid treatment reduces proinflammatory cytokines (TNF-α, IL-6, IL-1β), ROS production, lipid peroxidation, and intracellular Fe²⁺ in BV2 microglia.
- Uric acid increases antioxidant capacity and preserves mitochondrial ultrastructure in LPS or MPP+-stimulated BV2 microglia.
- In MPTP-induced Parkinson's disease mouse models, uric acid improves motor performance, preserves dopaminergic neuron density, and reduces neuroinflammation.
- Uric acid activates the Nrf2 signaling pathway and upregulates GPX4 expression, effects that are attenuated by the Nrf2 inhibitor ML385, confirming pathway specificity.
Clinical Significance
These findings suggest that uric acid may have therapeutic potential to alleviate neuroinflammation and ferroptosis in Parkinson's disease through activation of the Nrf2 pathway, potentially slowing disease progression.
Citation
Zhou Dongmei, Xiong Tian, Yang Binget al.. Uric acid alleviates the inflammatory response in LPS-induced BV2 cells and MPTP-induced PD mice by resisting ferroptosis through the Nrf2 signalling pathway. Redox report : communications in free radical research. 2026-Dec-31.