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

Autor: Oruc A; Department of Physiology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey. aykut.oruc@iuc.edu.tr., Oruc KY; Department of Physiology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey.; Department of Physiology, Faculty of Medicine, Istinye University, Istanbul, Turkey., Yanar K; Department of Medical Biochemistry, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey., Mengi M; Department of Physiology, Medical Faculty, Namık Kemal University, Tekirdag, Turkey., Caglar A; Department of Pathology, Bagcilar Training and Research Hospital, Istanbul, Turkey., Kurt BO; Department of Biophysics, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey., Altan M; Department of Physiology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey., Sonmez OF; Department of Physiology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey., Cakatay U; Department of Medical Biochemistry, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey., Uzun H; Department of Medical Biochemistry, Faculty of Medicine, Istanbul Atlas University, Istanbul, Turkey., Simsek G; Department of Physiology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey.
Jazyk: angličtina
Zdroj: Biological trace element research [Biol Trace Elem Res] 2024 Jan; Vol. 202 (1), pp. 233-245. Date of Electronic Publication: 2023 Apr 18.
DOI: 10.1007/s12011-023-03667-3
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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