In vivo, in silico effects of sakuranetin as a multi-target nutraceutical against PTZ-induced seizures via GABA restoration and BDNF/TrkB activation

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In vivo, in silico effects of sakuranetin as a multi-target nutraceutical against PTZ-induced seizures via GABA restoration and BDNF/TrkB activation

Scientific Reports , Article number:  (2025) Cite this article

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Abstract

Current antiepileptic drugs are effective in suppressing motor seizures; however, they often do not address the underlying factors such as oxidative stress, inflammation, and neurotrophic imbalances that contribute to the development of epilepsy. Recently, flavonoids sourced from diet have attracted attention as neuromodulators that can target these root causes. This study evaluated the protective effects of sakuranetin—a flavonoid found in edible Prunus species—against pentylenetetrazole (PTZ)-induced seizures and neurochemical changes in mice. Swiss albino mice (n = 6/group) were treated with saline, PTZ (35 mg/kg, intraperitoneally), or PTZ combined with sakuranetin (10 or 20 mg/kg, orally) every other day for 28 days. The study assessed seizure activity, oxidative stress markers, inflammatory cytokines, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and caspase-3 activity. Additionally, in silico docking and 100 ns molecular dynamics simulations were performed to investigate sakuranetin’s interactions with BDNF, TrkB, and D₂-like receptors. The results showed that sakuranetin treatment significantly improved seizure parameters. The onset latency was extended with both doses. The duration of clonic–tonic seizures was reduced by half, and mortality rates dropped from 50% to 8%. PTZ-induced reductions in neurotransmitters (such as GABA, dopamine, norepinephrine, serotonin, and acetylcholine) were restored, antioxidant defenses (including superoxide dismutase, catalase, and glutathione) were enhanced, and both lipid peroxidation (measured by malondialdehyde) and nitrosative stress (nitric oxide) were significantly decreased. Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were reduced, BDNF and TrkB levels approached control levels, and caspase-3 activity was diminished. Docking studies and MM-GBSA analyses indicated that BDNF was the most favorable binding partner for sakuranetin (with a binding free energy of approximately − 57 kcal/mol), and the simulations affirmed the stability of the complex. These findings suggest that sakuranetin has substantial, multi-target anticonvulsant effects by restoring neurotransmitter balance, enhancing antioxidant capacity, suppressing neuroinflammation, and revitalizing BDNF/TrkB signaling. Given its dietary origin, sakuranetin warrants further investigation as a potential nutraceutical candidate for managing epilepsy.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This research has been funded by the Scientific Research Deanship at the University of Ha’il – Saudi Arabia through project number RG-23 079.

Funding

This research has been funded by the Scientific Research Deanship at the University of Ha’il – Saudi Arabia through project number RG-23 079.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Ha’il, Ha’il, 81442, Saudi Arabia

    Rahamat Unissa Syed

  2. Department of Clinical Nutrition, College of Applied Medical Sciences, University of Ha’il, Ha’il, Kingdom of Saudi Arabia

    Humera Banu

  3. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Ha’il, Ha’il, 81442, Saudi Arabia

    Weam M. A. Khojali

  4. Department of Clinical Pharmacy, College of Pharmacy, University of Ha’il, Ha’il, Saudi Arabia

    Mhdia Elhadi Osman

  5. College of Pharmacy, University of Ha’il, Ha’il, 81442, Saudi Arabia

    Amal Mohammad Alrashidi

  6. College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia

    Lama Nasser

  7. Consultant Internal Medicine, King Salman Specialist Hospital, Ha’il, Saudi Arabia

    Huda Alzubir

  8. Specialist of Clinical Immunology and Allergy, King Salman Specialist Hospital, Ha’il, Saudi Arabia

    Amira Ibrahim Mohammed Ahmed Alfaki

  9. Department of Chemistry, College of Science, University of Ha’il, Ha’il, 81442, Saudi Arabia

    Najat Masood

  10. Department of Pharmacology, College of Pharmacy, University of Ha’il, Ha’il, 81442, Saudi Arabia

    Gehad M Subaiea

  11. Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia

    Ling Shing Wong

  12. Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, Kuala Lumpur, 56000, Malaysia

    Vinoth Kumarasamy

  13. Department of Medical Sciences, School of Medical and Life Sciences, Sunway University Jalan University, Bandar Sunway, Darul Ehsan, 47500, Selangor, Malaysia

    Vetriselvan Subramaniyan

Authors

  1. Rahamat Unissa Syed
  2. Humera Banu
  3. Weam M. A. Khojali
  4. Mhdia Elhadi Osman
  5. Amal Mohammad Alrashidi
  6. Lama Nasser
  7. Huda Alzubir
  8. Amira Ibrahim Mohammed Ahmed Alfaki
  9. Najat Masood
  10. Gehad M Subaiea
  11. Ling Shing Wong
  12. Vinoth Kumarasamy
  13. Vetriselvan Subramaniyan

Contributions

RUS, HB, and WMAK performed the behavioural experiments, data curation, formal analysis and edited the manuscript. MEO, AMA, LN, and HA contributed to the confocal analysis. AIMAA, NM, and GS reviewed and edited the manuscript. LSW, VK, and VS were responsible for the conceptualization, experimental design, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, supervision, validation, visualization, and manuscript writing (original draft, review, and editing). All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Rahamat Unissa Syed or Vinoth Kumarasamy.

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Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare no conflict of interest, financial or otherwise.

Ethics approval and consent to participate

The Kingdom of Saudia Arabia, Ministry of Education, University of Hail, and Research Ethics Committee, following ARRIVE guidelines, approved the experiment (H-2025-583; Jan 21, 2025).

Human and animal rights

All procedures performed in this study involving animals were conducted following national ethical standards for the protection of animals used for scientific purposes.

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Syed, R.U., Banu, H., Khojali, W.M.A. et al. In vivo, in silico effects of sakuranetin as a multi-target nutraceutical against PTZ-induced seizures via GABA restoration and BDNF/TrkB activation. Sci Rep (2025). https://doi.org/10.1038/s41598-025-26746-y

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