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The Role of Glycogen Synthase Kinase-3β in the Zinc-Mediated Neuroprotective Effect of Metformin in Rats with Glutamate Neurotoxicity

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Abstract

Metformin has been suggested to have protective effects on the central nervous system, but the mechanism is unknown. The similarity between the effects of metformin and the inhibition of glycogen synthase kinase (GSK)-3β suggests that metformin may inhibit GSK-3β. In addition, zinc is an important element that inhibits GSK-3β by phosphorylation. In this study, we investigated whether the effects of metformin on neuroprotection and neuronal survival were mediated by zinc-dependent inhibition of GSK-3β in rats with glutamate-induced neurotoxicity. Forty adult male rats were divided into 5 groups: control, glutamate, metformin + glutamate, zinc deficiency + glutamate, and zinc deficiency + metformin + glutamate. Zinc deficiency was induced with a zinc-poor pellet. Metformin was orally administered for 35 days. D-glutamic acid was intraperitoneally administered on the 35th day. On the 38th day, neurodegeneration was examined histopathologically, and the effects on neuronal protection and survival were evaluated via intracellular S-100β immunohistochemical staining. The findings were examined in relation to nonphosphorylated (active) GSK-3β levels and oxidative stress parameters in brain tissue and blood. Neurodegeneration was increased (p < 0.05) in rats fed a zinc-deficient diet. Active GSK-3β levels were increased in groups with neurodegeneration (p < 0.01). Decreased neurodegeneration, increased neuronal survival (p < 0.01), decreased active GSK-3β (p < 0.01) levels and oxidative stress parameters, and increased antioxidant parameters were observed in groups treated with metformin (p < 0.01). Metformin had fewer protective effects on rats fed a zinc-deficient diet. Metformin may exert neuroprotective effects and increase S-100β-mediated neuronal survival by zinc-dependent inhibition of GSK-3β during glutamate neurotoxicity.

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The raw data supporting this study will be available by authors to any qualified researcher upon request.

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Funding

This study was funded by the Istanbul University Scientific Research Projects. Project No: 27509.

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Authors and Affiliations

  1. Department of Physiology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey

    Aykut Oruc, Kadriye Yagmur Oruc, Mehmet Altan, Osman Fuat Sonmez & Gonul Simsek

  2. Department of Physiology, Faculty of Medicine, Istinye University, Istanbul, Turkey

    Kadriye Yagmur Oruc

  3. Department of Medical Biochemistry, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey

    Karolin Yanar & Ufuk Cakatay

  4. Department of Physiology, Medical Faculty, Namık Kemal University, Tekirdag, Turkey

    Murat Mengi

  5. Department of Pathology, Bagcilar Training and Research Hospital, Istanbul, Turkey

    Aysel Caglar

  6. Department of Biophysics, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey

    Bahar Ozturk Kurt

  7. Department of Medical Biochemistry, Faculty of Medicine, Istanbul Atlas University, Istanbul, Turkey

    Hafize Uzun

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Contributions

All authors contributed significantly to this research.

Conceived and designed the experiments and wrote the manuscript: AO, GS. Performed the experiments and analyzed the data: AO, KYO, KY, MM, MA, AC, BOK, OFS, UC, HU, GS. The corresponding author: AO. All authors have been involved in the drafting, critical revision, and final approval of the manuscript for publication. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Aykut Oruc.

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Ethical approval was obtained for the project from Istanbul University Animal Experiments Local Ethics Committee with the number 35980450–050.99. Guide for the Care and Use of Laboratory Animals of National Academy of Sciences was followed for caring animals during the experiment.

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Oruc, A., Oruc, K.Y., Yanar, K. et al. The Role of Glycogen Synthase Kinase-3β in the Zinc-Mediated Neuroprotective Effect of Metformin in Rats with Glutamate Neurotoxicity. Biol Trace Elem Res 202, 233–245 (2024). https://doi.org/10.1007/s12011-023-03667-3

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