Echinacoside exerts neuroprotection via suppressing microglial α-synuclein/TLR2/NF-κB/NLRP3 axis in parkinsonian models

Xue-Ping Yang; Jia-Hua Huang; Fan-Long Ye; Qing-Yun Yv; Sheng Chen; Wen-Wei Li; Min Zhu

doi:10.1016/j.phymed.2023.155230

Echinacoside exerts neuroprotection via suppressing microglial α-synuclein/TLR2/NF-κB/NLRP3 axis in parkinsonian models

Phytomedicine. 2024 Jan:123:155230. doi: 10.1016/j.phymed.2023.155230. Epub 2023 Nov 19.

Authors

Xue-Ping Yang¹, Jia-Hua Huang², Fan-Long Ye², Qing-Yun Yv², Sheng Chen², Wen-Wei Li³, Min Zhu⁴

Affiliations

¹ Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha 410000, PR China; Laboratory of Neuropathology and Neuropharmacology, Department of Neurology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201500, China; Institute of Neurology, Institutes of Integrative Medicine, Fudan University, Shanghai 201500, China.
² Laboratory of Neuropathology and Neuropharmacology, Department of Neurology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201500, China; Institute of Neurology, Institutes of Integrative Medicine, Fudan University, Shanghai 201500, China.
³ Laboratory of Neuropathology and Neuropharmacology, Department of Neurology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201500, China; Institute of Neurology, Institutes of Integrative Medicine, Fudan University, Shanghai 201500, China. Electronic address: wenweili2000@aliyun.com.
⁴ Shanghai Key Laboratory of Visual Impairment and Restoration, Eye & ENT Hospital, Fudan University, Shanghai 200031, China. Electronic address: min.zhu@fdeent.org.cn.

PMID: 38000105
DOI: 10.1016/j.phymed.2023.155230

Abstract

Background: Echinacoside (ECH), a natural active compound, was found to exert neuroprotection in Parkinson's disease (PD). However, the underlying molecular mechanisms remain controversial.

Purpose: This study aimed to explore the roles of ECH in PD and its engaged mechanisms.

Conclusion: In vivo, MPTP was adapted to construct subacute PD mouse model to explore the regulation of ECH on NLRP3 inflammasome. In vitro, α-synuclein (α-syn)/MPP⁺ was used to mediate the activation of NLRP3 inflammasome in BV2 cells, and the mechanism of ECH regulation of it was explored with molecular docking, immunofluorescence, Western blotting, and small molecule inhibitors.

Conclusion: The activation of microglial NLRP3 inflammasome could be evoked by MPTP in vitro, but its toxic metabolite MPP⁺ alone cannot trigger the activation of NLRP3 inflammasome in vitro, which requires α-synuclein (α-syn) priming. Exogenous α-syn could evoke microglial TLR2/NF-κB/NLRP3 axis, playing the priming role in MPP⁺ -mediated NLRP3 inflammasome activation. ECH can suppress the upregulation of α-syn in MPTP-treated mice and BV2 microglia. It can also suppress the activation of the TLR2/NF-κB/NLRP3 axis induced by α-syn.

Conclusion: ECH exerts neuroprotective effects by downregulating the TLR2/NF-κB/NLRP3 axis via reducing the expression of α-syn in the PD models.

Keywords: Echinacoside; Microglia; Nlrp3 inflammasone; Parkinson's disease; Toll-like receptor 2; Α-synuclein.

MeSH terms

Animals
Glycosides*
Inflammasomes
Mice
Mice, Inbred C57BL
Microglia
Molecular Docking Simulation
NF-kappa B / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
Neuroprotection
Parkinson Disease* / drug therapy
Parkinson Disease* / metabolism
Toll-Like Receptor 2 / metabolism
alpha-Synuclein / metabolism

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
Inflammasomes
NF-kappa B
alpha-Synuclein
echinacoside
Toll-Like Receptor 2
Glycosides