Anti-Ischemic and Antioxidant Activity of the Pharmacological Agonist of Galanin Receptor GalR2 and Carnosine in In Vitro and In Vivo Model Systems

Abstract

Antioxidant and anti-ischemic properties of the pharmacological agonist of galanin receptor GalR2 WTLNSAGYLLGPβAH (Gal) and its C-terminal fragment, dipeptide carnosine (βAH), have been studied in the model of regional ischemia and reperfusion of a rat heart in vivo in the dose range of 0.5–5.0 mg/kg and Сu²⁺-induced free radical oxidation of low-density lipoproteins (LDLs) of human plasma in vitro for peptide concentrations of 0.01 mM and 0.1 mM. Gal was obtained by automatic solid phase synthesis using the Fmoc methodology; its structure was characterized by ¹H-NMR spectroscopy and MALDI-TOF mass spectrometry. Intravenous administration of the optimal dose of Gal (1 mg/kg) to rats after ischemia was more effective than carnosine at reducing the myocardial infarct size and the activity of creatine kinase-MB and lactate dehydrogenase in blood plasma at the end of reperfusion. It also improved the metabolic state of the reperfused myocardium and decreased the formation of peroxidation products during reperfusion. Gal reduced more effectively the formation of adducts of hydroxyl radicals in the interstitium of the area at risk (AAR) of the rat heart than carnosine. Carnosine at a dose of 1 mg/kg more effectively increased the activity of catalase and glutathione peroxidase in the AAR by the end of reperfusion compared to Gal. In the model of Cu²⁺-initiated oxidation of human plasma LDLs 0.1 mM, carnosine demonstrated a significantly more pronounced reduction in the formation of lipid radicals compared to Gal. The results show that Gal can be viewed as a promising agent that reduces myocardial injury during reperfusion and oxidative stress.