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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2020

Open Access 01-12-2020 | Research

Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress

Authors: Dongjie Peng, Junyan Li, Yue Deng, Xiaojuan Zhu, Lin Zhao, Yuwen Zhang, Zhaocong Li, Shiyan Ou, Shaojun Li, Yueming Jiang

Published in: Journal of Neuroinflammation | Issue 1/2020

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Abstract

Background

The activation of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent pyroptosis has been shown to play a vital role in the pathology of manganese (Mn)-induced neurotoxicity. Sodium para-aminosalicylic acid (PAS-Na) has a positive effect on the treatment of manganism. However, the mechanism is still unclear. We hypothesized that PAS-Na might act through NLRP3.

Methods

The microglial cell line BV2 and male Sprague-Dawley rats were used to investigate the impacts of PAS-Na on Mn-induced NLRP3 inflammasome-dependent pyroptosis. The related protein of the NF-κB pathway and NLRP3-inflammasome-dependent pyroptosis was detected by western blot. The reactive oxygen species and mitochondrial membrane potential were detected by immunofluorescence staining and flow cytometry. The activation of microglia and the gasdermin D (GSDMD) were detected by immunofluorescence staining.

Results

Our results showed that Mn treatment induced oxidative stress and activated the NF-κB pathway by increasing the phosphorylation of p65 and IkB-α in BV2 cells and in the basal ganglia of rats. PAS-Na could alleviate Mn-induced oxidative stress damage by inhibiting ROS generation, increasing mitochondrial membrane potential and ATP levels, thereby reducing the phosphorylation of p65 and IkB-α. Besides, Mn treatment could activate the NLRP3 pathway and promote the secretion of IL-18 and IL-1β, mediating pyroptosis in BV2 cells and in the basal ganglia and hippocampus of rats. But an inhibitor of NF-κb (JSH-23) treatment could significantly reduce LDH release, the expression of NLRP3 and Cleaved CASP1 protein and IL-1β and IL-18 mRNA level in BV2 cells. Interestingly, the effect of PAS-Na treatment in Mn-treated BV2 cells is similar to those of JSH-23. Besides, immunofluorescence results showed that PAS-Na reduced the increase number of activated microglia, which stained positively for GSDMD.

Conclusion

PAS-Na antagonized Mn-induced NLRP3 inflammasome dependent pyroptosis through inhibiting NF-κB pathway activation and oxidative stress.
Appendix
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Metadata
Title
Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress
Authors
Dongjie Peng
Junyan Li
Yue Deng
Xiaojuan Zhu
Lin Zhao
Yuwen Zhang
Zhaocong Li
Shiyan Ou
Shaojun Li
Yueming Jiang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-020-02018-6

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