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Salsolinol Induces Parkinson’s Disease Through Activating NLRP3-Dependent Pyroptosis and the Neuroprotective Effect of Acteoside

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Abstract

Endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline (Salsolinol, SAL) is a dopamine metabolite that is toxic to dopaminergic neurons in vitro and in vivo, and is involved in the pathogenesis of Parkinson’s disease (PD). However, the molecular mechanism by which SAL induces neurotoxicity in PD remains challenging for future investigations. This study found that SAL induced neurotoxicity in SH-SY5Y cells and mice. RNA sequencing (RNAseq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to detect differentially expressed genes in SAL-treated SH-SY5Y cells. We found that NLR family pyrin domain-containing 3 (NLRP3)-dependent pyroptosis was enriched by SAL, which was validated by in vitro and in vivo SAL models. Further, NLRP3 inflammasome-related genes (ASC, NLRP3, active caspase 1, IL-1β, and IL-18) were increased at the mRNA and protein level. Acteoside mitigates SAL-induced neurotoxicity by inhibiting NLRP3 inflammasome-related pyroptosis in in vitro and in vivo PD models. In summary, the present study suggests for the first time that NLRP3-dependent pyroptosis plays a role in the pathogenesis of SAL-induced PD, and acteoside mitigates SAL-induced pyroptosis-dependent neurotoxicity in in vitro and in vivo PD models. The present results demonstrated a new mechanism whereby SAL mediates neurotoxicity by activating NLRP3-dependent pyroptosis, further highlighting SAL-induced pyroptosis-dependent neurotoxicity as a potential therapeutic target in PD.

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Data Availability

All data generated or analyzed during this study are included in this published article and its additional files.

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Funding

This work was supported in part by the National Natural Science Foundation of China (81260196, 81450036), the Science Foundation of AMHT (2020YK02, 2021YK05), the Science Foundation of CASIC (2020-LCYL-009), the Science Foundation of ASCH (YN202104), the Hygiene and Health Development Scientific Research Fostering Plan of Haidian District Beijing (HP2021-19–50701), the Natural Science Foundation of Inner Mongolia Autonomous Region (IMAR) (2021MS08131, 2020MS08175, 2021LHMS08024, 2022MS08046), and the Foundation of Inner Mongolia Minzu University (NMGSS2128).

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  1. Yumin Wang and Shuang Wu equally contributed to this work.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China

    Yumin Wang

  2. Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China

    Shuang Wu

  3. Department of Neurology, The Affiliated Hospital of Chifeng University, Chifeng, 024005, China

    Qiang Li & Wenjing Li

  4. Department of Psychological Medicine, The Affiliated Hospital of Chifeng University, Chifeng, 024005, People’s Republic of China

    Weihong Lang

  5. Department of Anatomy, College of Basic Medicine, Chifeng University Health Science Center, Chifeng, 024005, China

    Xiaodong Jiang

  6. Department of Neurology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China

    Zhirong Wan

  7. Chifeng University Health Science Center, Chifeng, 024000, China

    Huiyan Sun

  8. Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for CancerTianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China

    Hongquan Wang

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  1. Yumin Wang
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Contributions

YW, SW, and HW conceived of and designed the study, and HW provided administrative support. YW, SW, and HW wrote the manuscript. All authors analyzed and interpreted the data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Huiyan Sun or Hongquan Wang.

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This study was carried out in accordance with the principles of the Basel Declaration and recommendations of Aerospace Center Hospital for laboratory animals. The animal study was reviewed and approved by medical ethics committee of Aerospace Center Hospital.

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Wang, Y., Wu, S., Li, Q. et al. Salsolinol Induces Parkinson’s Disease Through Activating NLRP3-Dependent Pyroptosis and the Neuroprotective Effect of Acteoside. Neurotox Res 40, 1948–1962 (2022). https://doi.org/10.1007/s12640-022-00608-1

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