Cardiometabolic Efficacy and Toxicological Evaluation of a Pharmacological Galanin Receptor Agonist
The goal of this study was to examine effects of a novel galanin receptor agonist GalR1-3 [βAla14, His15]-galanine 2-15 (G), obtained by automatic solid-phase peptide synthesis, on the metabolic state of the area at risk and the size of acute myocardial infarction (MI) in rats in vivo and to evaluate its toxicity in BALB/c mice after a single dose administration. Regional ischemia was induced in anesthetized rats by coronary artery occlusion followed by restoration of coronary blood flow. The peptide G was administered intravenously (i.v.) with a bolus after a period of regional ischemia in the dose range of 0.25–3.0 mg/kg. The sizes of MI and activities of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in blood plasma were evaluated. The effect of administration of the optimal dose of G (1.0 mg/kg) on the myocardial content of adenine nucleotides (AN), phosphocreatine (PCr), creatine (Cr), and lactate was studied. The peptide G toxicity was evaluated after a single intraperitoneal injection of 0.5–3.0% solution of the peptide substance to mice. The i.v. administration of the optimal dose of G to rats (1.0 mg/kg) insignificantly influenced hemodynamic parameters, but reduced the MI size by 40% and decreased plasma LDH and CK-MB activity by the end of reperfusion as compared to control. These effects were accompanied by a significant improvement in the metabolic state of the area at risk (AAR) as evidenced by an increase in the myocardial content of ATP, ΣAN, PCr and ΣCr, and a decrease in the myocardial lactate level compared to control. The absence of signs of intoxication and death of animals after G injection of the maximum possible dose did not allow determining an LD50 dose. The results of this study indicate a therapeutic potential of the peptide G for preventing myocardial ischemia and reperfusion injury and a clear need for further studies of its pharmacological properties and mechanisms of action.
Keywords:galanin rat myocardial ischemia and reperfusion myocardial energy metabolism toxicity
This work was supported by the Russian Foundation for Basic Research (project nos. 18-015-00008 and 18-015-00009).
COMPLIANCE WITH ETHICAL STANDARDS
The study was carried out in accordance with the “International Recommendations for Biomedical Research Using Animals” approved by the Council for International Organizations of Medical Sciences (CIOMS) in 1985 (Geneva).
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