Aim of the study
To explore the role of PIP in regulating the gut-brain autophagy signaling pathway to reduce α-Syn levels in both the colon and substantia nigra (SN) of PD model rats. Materials and
Conclusions
Our findings suggested that PIP could protect neurons by activating autophagy to degrade α-Syn in the SN and colon, which were related to the suppression of PIP on the activation of PI3K/AKT/mTOR signaling pathway.
Methods
Behavioral experiments were conducted to assess the impact of PIP on 6-hydroxydopamine (6-OHDA)-induced PD rats. The intestinal microbiome composition and intestinal metabolites were analyzed by metagenomics and GC-MS/MS. The auto-phagosomes were visualized by transmission electron microscopy. Immunohistochemistry, immunofluorescence, and western blotting were performed to assess the levels of tyrosine hydroxylase (TH), α-Syn, LC3II/LC3I, p62, and the PI3K/AKT/mTOR pathway in both the SN and colon of the rats. The pathway-related inhibitor and agonist were used to verify the autophagy mechanism in the SH-SY5Y cells overexpressing A53T mutant α-Syn (A53T-α-Syn).
Results
PIP improved autonomic movement and gastrointestinal dysfunctions, reduced α-Syn aggregation and attenuated the loss of dopaminergic neurons in 6-OHDA-induced PD rats. After oral administration of PIP, the radio of LC3II/LC3I increased and the expression of p62 was degraded, as well as the phosphorylation levels of PI3K, AKT and mTOR decreased in the SN and colon of rats. The effect of PIP on reducing A53T-α-Syn through the activation of the PI3K/AKT/mTOR-mediated autophagy pathway was further confirmed in A53T-α-Syn transgenic SH-SY5Y cells. This effect could be inhibited by the autophagy inhibitor bafilomycin A1 and the PI3K agonist 740 Y-P. Conclusions: Our findings suggested that PIP could protect neurons by activating autophagy to degrade α-Syn in the SN and colon, which were related to the suppression of PIP on the activation of PI3K/AKT/mTOR signaling pathway.