Exploration of the effects of astragaloside Ⅳ and its analogues on improving Parkinson's disease based on "indirect regulation"

This study is based on the "indirect regulation" strategy to explore the effects of astragaloside Ⅳ (AG) and its analogs cycloastragenol (CAG) and astragenol (HG) in regulating the gut microbiota to improve Parkinson's disease (PD). Through the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mouse model, combined with behavioral experiments, immunofluorescence staining, Western blot, and 16S rRNA sequencing, the therapeutic effects and potential mechanisms of the three compounds were systematically evaluated (the animal experiment was approved by the Animal Medical Ethics Committee of Shanxi University of Chinese Medicine, the approval number is AWE202307367). The results showed that AG, CAG, and HG (30 mg·kg^-1) could significantly improve the behavioral phenotypes such as gait abnormalities and bradykinesia in PD mice, and restore the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra region, and inhibit the expression of ionized calcium binding adapter molecule 1 (Iba-1), a marker of microglial cell activation. Among them, CAG had the best effect among the three, which was comparable to that of the positive drug levodopa (70 mg·kg^-1). The analysis of the gut microbiota indicated that all three compounds could reverse the decrease in microbiota diversity induced by MPTP and adjust the abundances of PD disease-related genera Akkermansia, Lactobacillus, and Ruminococcus. AG specifically promoted the enrichment of the genus Allobaculum, while CAG and HG significantly increased the abundance of the genus Blautia, suggesting that they inhibited neuroinflammation by regulating microbiota metabolites (such as short-chain fatty acids). The study demonstrates that AG, CAG, and HG can indirectly regulate the structure of the gut microbiota through the "gut-brain axis" and inhibit central neuroinflammation, thus improving the pathological process of PD. This provides a multi-target intervention strategy based on natural products for the treatment of PD.