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

Abstract

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