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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1510337
This article is part of the Research Topic Plant and Fungal Extracts and Metabolites in Neurotherapy: Exploring Their Pharmacology and Potential Clinical Uses View all 8 articles

Exploring the Potential Anti-Senescence Effects of Soybean-derived Peptide Soymetide in Mice Hippocampal Neurons via the Wnt/β-Catenin Pathway

Provisionally accepted
Asmita Garg Asmita Garg 1,2*Jyotshana Saroj Jyotshana Saroj 2,3*Saurabh Tiwari Saurabh Tiwari 1,2*Uttara Das Uttara Das 1,2*Neetu Shukla Neetu Shukla 1,2*Jimut Kanti Ghosh Jimut Kanti Ghosh 2,3*Sanghamitra Bandyopadhyay Sanghamitra Bandyopadhyay 1,2*
  • 1 Indian Institute of Toxicology Research (CSIR), Lucknow, India
  • 2 Academy of Scientific and Innovative Research, Ghaziabad, India
  • 3 Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India

The final, formatted version of the article will be published soon.

    Soybean-based foods enhance cognitive functions by influencing hippocampal mechanisms. These salutary effects have so far been attributed to isoflavones present in soybeans. Considering cellular senescence contributes to cognitive decline and that no specific soy-derived peptides are known for their potential to mitigate senescence, we examined the efficacy of a thirteen amino acid soy-derived peptide, Soymetide, on a doxorubicin-induced senescence mice model. Soymetide pretreatment lowered the senescence markers p53, p21 and p16, pro-inflammatory cytokines, and Senescence β-Galactosidase staining while enhancing the mature neuronal marker NeuN in the hippocampus. This anti-senescent effect was comparable with that of a well-known senolytic combination (dasatinib and quercetin). Research indicates that Wnt signaling influences cellular senescence, and our findings here demonstrate that doxorubicin decreased hippocampal Wnt3a, p-LRP6, Frizzled, Dishevelled, Axin1, and β-catenin levels and increased GSK-3β, while Soymetide mitigated these effects. Additionally, upon inhibition of the Wnt/β-catenin pathway, Soymetide’s ability to reduce senescence markers and restore NeuN expression was reduced. We validated the anti-senescence impact on hippocampal neurons by co-immunostaining Wnt/β-catenin and senescence indicators alongside NeuN in mice and assessed it in primary hippocampal neurons. Further examining the neuronal survival and functions revealed that Soymetide blocked the doxorubicin-induced loss in Nissl-stained surviving neurons and learning-memory performances, measured by Y-Maze and Passive Avoidance tests, which Wnt/β-catenin inhibitors could counteract. In conclusion, our study identifies a novel Wnt/β-catenin-linked mechanism of doxorubicin-induced senescence in the hippocampal neurons and demonstrates Soymetide's effectiveness in reversing this process. Hence, this suggests Soymetide’s potential therapeutic application in addressing cognitive decline associated with cellular aging.

    Keywords: Soymetide, senescence, Doxorubicin, Wnt/β-Catenin pathway, Hippocampus, neuroprotection Soymetide, Neuroprotection

    Received: 12 Oct 2024; Accepted: 13 Jan 2025.

    Copyright: © 2025 Garg, Saroj, Tiwari, Das, Shukla, Kanti Ghosh and Bandyopadhyay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Asmita Garg, Indian Institute of Toxicology Research (CSIR), Lucknow, India
    Jyotshana Saroj, Central Drug Research Institute (CSIR), Lucknow, 226031, Uttar Pradesh, India
    Saurabh Tiwari, Indian Institute of Toxicology Research (CSIR), Lucknow, India
    Uttara Das, Indian Institute of Toxicology Research (CSIR), Lucknow, India
    Neetu Shukla, Indian Institute of Toxicology Research (CSIR), Lucknow, India
    Jimut Kanti Ghosh, Central Drug Research Institute (CSIR), Lucknow, 226031, Uttar Pradesh, India
    Sanghamitra Bandyopadhyay, Indian Institute of Toxicology Research (CSIR), Lucknow, India

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