Nucleolin inhibits α-synuclein to attenuate aconitine's neurotoxicity

  • Phytomedicine. 2025 Aug:144:156932. doi: 10.1016/j.phymed.2025.156932.
Guangxin Liu  1 ,  Wenqiang Zuo  2 ,  Zhen Zhang  3 ,  Wenbo Lv  4 ,  Tong Xu  5 ,  Ting Ma  4 ,  Wugang Hou  2 ,  Anqi Geng  6 ,  Yi Zhang  7
Affiliations
  • 1. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China; School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China; Sanhang Institute for Brain Science and Technology, Northwestern Polytechnical University, Xi'an 710129, PR China.
  • 2. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Air Force Medical University, Xi'an 710032, PR China.
  • 3. Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710129, PR China.
  • 4. Sanhang Institute for Brain Science and Technology, Northwestern Polytechnical University, Xi'an 710129, PR China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710129, PR China.
  • 5. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China; School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
  • 6. Sanhang Institute for Brain Science and Technology, Northwestern Polytechnical University, Xi'an 710129, PR China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710129, PR China; Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 88460825, PR China. Electronic address: [email protected].
  • 7. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China; School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China. Electronic address: [email protected].
PMID: 40482618 DOI: 10.1016/j.phymed.2025.156932
Abstract

Background: Aconitine (AC), a toxic alkaloid derived from Aconitum species, presents a significant risk of neurotoxicity with global poisoning reports.

Purpose: This study aimed to reveal the mechanism underlying the neurotoxicity of AC.

Methods: The toxicity of AC was evaluated by behavioral tests, histological examinations, western blot (WB) and immunofluorescence. We studied its potential mechanism through transcriptome, proteomics, nascent transcripts and immunoprecipitation/mass spectrometry (IP/MS).

Results: AC caused motor dysfunction and anxiety-like behaviors. And the peak of Pyroptosis occurred at 8 h, accompanied by abnormal neurotransmitter-related metabolite expressions in brain tissue, ultrastructural damage and morphological changes in neurons. Importantly, transcriptomic and proteomic analyses indicate the elevation of α-synuclein (α-syn) level and the activation of the PI3K/Akt/mTOR pathway are key drivers of AC neurotoxicity. IP/MS further elucidated that nucleolin (Ncl) is essential for clearing p-α-syn (Ser129). The nascent transcript discovered that the peaks of nascent mRNA of Snca and Ncl appeared at 8 h after AC exposure. Meanwhile, we verified that AC activates the PI3K/Akt/mTOR pathway. Moreover, the hypothesis that Ncl is involved in reducing neurotoxicity by antagonizing AC - induced elevation of α-syn has been further verified in WB and motor behavior studies.

Conclusion: Our work reveals that the neurotoxicity induced by AC is attributed to the abnormal elevation of α-syn, and nucleolin has a clearance effect.

Keywords
Aconitine; Neurotoxicity; Nucleolin; Pyroptosis; α-Synuclein.
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