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

Metformin has been suggested to have protective effects on the central nervous system with an unclarified mechanism. 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, it was 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, Zinc Deficiency + Metformin + Glutamate. Zinc deficiency was induced with a zinc-poor pellet. Metformin was given orally for 35 days. D-glutamic acid was administered intraperitonally on the 35th day. On the 38th day, neurodegeneration was examined histopathologically and effects on neuronal protection and survival were evaluated via intracellular S-100β immunohistochemical staining. The findings were examined in relation to non-phosphorylated (active) GSK-3β levels and oxidative stress parameters observed in brain tissue and blood. Neurodegeneration was higher (p < 0.05) in rats fed with an inadequate zinc diet. Active GSK-3β levels were increased in groups with neurodegeneration (p < 0.01). Decreased neurodegeneration and 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 less protective effects in rats fed with an inadequate zinc diet. Metformin may demonstrate its neuroprotective effects and may increase S-100β mediated neuronal survival by a zinc-dependent inhibition of GSK-3β in glutamate neurotoxicity.