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Protective Effects of Glycyl-Glutamine Dipeptide on in Vitro Brain Ischemia Reperfusion Model and the Role of Sigma-1
Gülce Sevdar Çeçen1, Sümeyye Keskin1, Mustafa Sertaç Yılmaz1
1Bursa Uludag University, Faculty of Medicine, Department of Pharmacology, Bursa, Türkiye.
Background:
Cerebral ischemia-reperfusion injury is characterized by oxidative stress, inflammation, and apoptotic cell death, which results in tissue damage. Although the Glycyl-Glutamine (Gly-Gln) dipeptide has primarily been investigated as a glutamine donor, its direct pharmacological effects and underlying mechanisms remain poorly defined.
Methods:
In this study, the effects of Gly-Gln on tissue viability and biochemical parameters were investigated using an in vitro model of cerebral ischemia-reperfusion injury. Dose-response analysis was performed using 2,3,5-triphenyltetrazolium chloride (TTC) staining to determine the minimum effective concentration of Gly-Gln. To assess whether the observed effects were specific to the dipeptide, equimolar concentrations of its degradation products, glycine and glutamine, were also evaluated. Oxidative stress and apoptotic markers were analyzed, and the potential involvement of sigma receptor ligands was examined.
Results:
Gly-Gln improved tissue viability in a dose-dependent manner, with 1,000 µM identified as the minimum effective concentration. Equimolar administration of glycine or glutamine did not produce comparable protective effects, indicating that the observed actions were specific to the intact dipeptide. Ischemia-reperfusion significantly increased lipid peroxidation and disrupted antioxidant balance, as evidenced by elevated malondialdehyde levels and reduced glutathione content. Although Gly-Gln alone did not significantly attenuate lipid peroxidation at the tested concentration, modulation of sigma-1 receptors markedly reduced oxidative damage. Apoptotic activity was increased following ischemia-reperfusion, whereas sigma receptor agonist treatment decreased the expression of apoptotic markers.
Conclusion:
In conclusion, Gly-Gln exerts direct, dose-dependent protective effects on tissue viability in cerebral ischemia-reperfusion injury, independently of its degradation products, and sigma-1 receptors may contribute to the underlying mechanisms.
