2. Academic Validation
  3. Piperine promotes PI3K/AKT/mTOR-mediated gut-brain autophagy to degrade α-Synuclein in Parkinson's disease rats

Piperine promotes PI3K/AKT/mTOR-mediated gut-brain autophagy to degrade α-Synuclein in Parkinson's disease rats

  • J Ethnopharmacol. 2023 Dec 27:322:117628. doi: 10.1016/j.jep.2023.117628.
Lan Yu 1,  Xiaolu Hu 2,  Rongrong Xu 3,  Yimeng Zhao 2,  Lijuan Xiong 2,  Jiaxuan Ai 2,  Xing Wang 2,  Xiaoqing Chen 2,  Yinying Ba 2,  Zhikai Xing 4,  Chongye Guo 4,  Shuangli Mi 5,  Xia Wu 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
  • 2 Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
  • 3 Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, China.
  • 4 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, 100101, China.
  • 5 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, 100101, China. Electronic address: [email protected].
  • 6 Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China. Electronic address: [email protected].
PMID: 38158101 DOI: 10.1016/j.jep.2023.117628
Abstract

Ethnopharmacological relevance: Piper longum L., a medicinal and food homologous herb, has a traditional history of use in treating gastrointestinal and neurological disorders. Piperine (PIP) the main alkaloid of P. longum, exists neuroprotective effects on various animal models of Parkinson's disease (PD). Nevertheless, the underlying mechanism, particularly the role of PIP in promoting gut-brain Autophagy for α-synuclein (α-Syn) degradation in PD, remains incompletely understood.

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 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.

Keywords

Gut-brain autophagy; PI3K/AKT/mTOR signaling pathway; Parkinson’s disease; Piperine; α-Synuclein.

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