Oruc, AykutOruc, Kadriye YagmurYanar, KarolinMengi, MuratCaglar, AyselKurt, Bahar OzturkAltan, Mehmet2024-05-192024-05-1920240163-49841559-0720https://doi.org10.1007/s12011-023-03667-3https://hdl.handle.net/20.500.12713/5175Metformin 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)-3 beta suggests that metformin may inhibit GSK-3 beta. In addition, zinc is an important element that inhibits GSK-3 beta 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-3 beta 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-100 beta immunohistochemical staining. The findings were examined in relation to nonphosphorylated (active) GSK-3 beta 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-3 beta levels were increased in groups with neurodegeneration (p < 0.01). Decreased neurodegeneration, increased neuronal survival (p < 0.01), decreased active GSK-3 beta ( 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-100 beta-mediated neuronal survival by zinc-dependent inhibition of GSK-3 beta during glutamate neurotoxicity.eninfo:eu-repo/semantics/openAccessGlutamateGsk-3 BetaMetforminNeurotoxicityS-100 BetaZincArticle202123324537071257WOS:0009745384000012-s2.0-85153106058N/A10.1007/s12011-023-03667-3Q1