Saikosaponin A mitigates the progression of Parkinson’s disease via attenuating microglial neuroinflammation through TLR4/MyD88/NF-κB pathway

X.-L. Liu, L. Fan, B.-H. Yue, Z. Lou

Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou City, Hebei Province, China. Xing198501@163.com

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• Neurology

OBJECTIVE: Neuroinflammation caused by excessive microglial cell activation and the subsequent death of dopaminergic neurons plays a role in the pathogenesis of Parkinson’s disease (PD). Saikosaponin A (Ssa), a triterpene saponin derived from Radix Bupleuri, has anti-inflammatory and antioxidant functions. This research aimed to investigate whether Ssa has a therapeutic effect on PD.

MATERIALS AND METHODS: BV2 microglia- and SH-SY5Y cells were treated with a neurotoxin N-methyl-4- phenylpyridinium (MPP+) and Ssa. Cell viability, apoptosis, inflammatory reactions, and expression levels of oxidative stress mediators were assessed. A PD rat model was created by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by the Ssa treatment. Hematoxylin-eosin (H&E) staining, Nissl staining, and immunohistochemistry were used to detect neuronal apoptosis and microglial activation. Open-field test (OFT) was performed to evaluate the locomotion of the rats. The underlying mechanism of Ssa effect in PD was explored using network pharmacology analysis and verified experimentally.

RESULTS: Ssa dampened neuronal apoptosis and had anti-inflammatory and anti-oxidative stress proprieties in MPP+-treated SH-SY5Y cells and BV2 microglia. As shown in in-vivo experiments, Ssa reduced MPTP-mediated neuronal apoptosis and motor dysfunction and lowered the expression of inflammatory factors and oxidative stressors in the substantia nigra (SN) of the PD rat. Additionally, Ssa inactivated the TLR4/MyD88/NF-κB pathway.

CONCLUSIONS: This study provides the first evidence that Ssa prevents dopaminergic neurodegeneration caused by microglia activation by modulating the TLR4/MyD88/NF-κB axis.

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