The effect of the azolo-triazine derivative AB-19 on the development of diabetic cardiomyopathy in rats

Natalia A. Gurova; Vadim A. Kosolapov; Alexey V. Smirnov; Denis A. Babkov; Valentina A.  Babkova; Alena S. Taran; Nikolay G. Panshin; Svetlana K. Kotovskaya; Irina M. Sapozhnikova; Vladimir L. Rusinov; Alexander A. Spasov

doi:10.18413/rrpharmacology.12.1049

Authors

Natalia A. Gurova Volgograd State Medical University https://orcid.org/0000-0002-0670-1444
Vadim A. Kosolapov tive Medicines, Volgograd State Medical University, https://orcid.org/0000-0002-6702-1207
Alexey V. Smirnov Volgograd State Medical University https://orcid.org/0000-0001-5351-6105
Denis A. Babkov Volgograd State Medical University https://orcid.org/0000-0002-9645-3324
Valentina A. Babkova Volgograd State Medical University https://orcid.org/0000-0003-1738-0567
Alena S. Taran Volgograd State Medical University https://orcid.org/0000-0001-8477-254X
Nikolay G. Panshin Volgograd State Medical University https://orcid.org/0000-0002-4035-4108
Svetlana K. Kotovskaya Ural Federal University named after the first President of Russia Boris N. Yeltsin https://orcid.org/0000-0002-3213-9838
Irina M. Sapozhnikova Ural Federal University Named after the First President of Russia B. N. Yeltsin https://orcid.org/0000-0002-5193-9670
Vladimir L. Rusinov Ural Federal University Named after the First President of Russia B. N. Yeltsin https://orcid.org/0000-0002-1705-4078
Alexander A. Spasov Volgograd State Medical University https://orcid.org/0000-0002-7185-4826

DOI:

https://doi.org/10.18413/rrpharmacology.12.1049

Abstract

Introduction: Cardiovascular diseases, including cardiomyopathies associated with endothelial dysfunction and impaired protein glycation, are the predominant cause of mortality in diabetes mellitus. This article presents data on the identification of functional and structural changes occurring during the development of diabetic cardiomyopathy and investigates the cardioprotective effects of the anti-glycating agents – the azolo-triazine derivative AB-19 and aminoguanidine.

Materials and Methods: Diabetic cardiomyopathy was modeled using streptozotocin 45 mg/kg I.V. on 60 male Sprague-Dawley rats. Aminoguanidine was investigated at the dose of 50 mg/kg and compound AB-19 – 20 mg/kg once daily. Observations were conducted over a period of 12 weeks. Blood glucose levels and glycated hemoglobin concentration were monitored. Upon completion of the diabetic cardiomyopathy induction period, the following were studied: endothelioprotective properties, cardiac contractile activity, solubility of tail tendon collagen and morphological examinations of the heart and myocardial blood vessels.

Results: The oral administration of AB-19 (20 mg/kg) and aminoguanidine (50 mg/kg) to animals with experimental diabetes mellitus resulted in a 17% reduction in blood HbA1c levels compared to that in the diabetic control rats. This treatment also limited the increase in AGEs in the blood by 51% and 39%, improved the solubility of collagen by 42% and 51%, respectively, restored endothelium-dependent vascular reactivity, and attenuated manifestations of left ventricular diastolic dysfunction associated with myocardial hypertrophy and fibrosis in diabetic animals. These findings were morphologically corroborated: animals treated with AB-19 and aminoguanidine exhibited a reduction in perivascular connective tissue, a decrease in collagen fibers in the myocardium, and a lower expression of AGEs and RAGE in IHC analysis using primary antibodies against AGEs and RAGE compared to the diabetic control group.

Conclusion: Compound AB-19 (20 mg/kg once daily) attenuates functional and structural manifestations of diabetic cardiomyopathy.

Graphical Abstract

Keywords:

azolo-triazines, antiglycation, late complications of diabetes mellitus, diabetic cardiomyopathy

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Author Contribution

Natalia A. Gurova, Volgograd State Medical University

Doctor Habil. of Medical Sciences (DSc), Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: vlgmed@mail.ru; ORCID ID: https://orcid.org/0000-0002-0670-1444. The author took part in conducting experimental work and analyzing the material, analyzed the results, and edited the text of the article.

Vadim A. Kosolapov, tive Medicines, Volgograd State Medical University,

Doctor Habil. of Medical Sciences (DSc), Professor of the Department of Pharmacology and Bioinformatics, Head of Laboratory for Metabotropic Drugs of Scientific Center for Innovative Medicines, Volgograd State Medical University, Volgograd, Russia; e-mail: vad-ak@mail.ru; ORCID ID: https://orcid.org/0000-0002-6702-1207. The author advised on the design of the study, analyzed the results, and edited the text of the article.

Alexey V. Smirnov, Volgograd State Medical University

Doctor Habil. of Medical Sciences (DSc), Professor, Head of the Department of Pathological Anatomy, Volgograd State Medical University, Volgograd, Russia; e-mail: alexey-smirnov@rambler.ru; ORCID ID: https://orcid.org/0000-0002-6702-1207. The author advised on the design of the study, analyzed the results and edited the text of the article.

Denis A. Babkov, Volgograd State Medical University

Doctor of Pharmaceutical Sciences (DSc), Professor of the Department of Pharmacology and Bioinformatics, Head of Scientific Center for Innovative Medicines, Volgograd State Medical University, Volgograd, Russia; e-mail: a.babkov@gmail.com; ORCID ID: https://orcid.org/0000-0002-9645-3324. The author took part in conducting experimental work and analyzing the material.

Valentina A. Babkova, Volgograd State Medical University

Candidate of Medical Sciences (PhD), Senior researcher, Scientific Center for Innovative Medicines, Volgograd State Medical University, Volgograd, Russia; e-mail: sysoeva_va@mail.ru; ORCID ID: https://orcid.org/0000-0003-1738-0567. The author took part in conducting experimental work and analyzing the material.

Alena S. Taran, Volgograd State Medical University

Candidate of Medical Sciences (PhD), Assistant Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: alena-beretta-taran@mail.ru; ORCID ID: https://orcid.org/0000-0001-8477-254X. The author was engaged in conducting the experimental work.

Nikolay G. Panshin, Volgograd State Medical University

Candidate of Medical Sciences (PhD), Assistant Professor of the Department of Pathological Anatomy, Volgograd State Medical University, Volgograd, Russia; e-mail: nickolay@gmail.com; ORCID ID: https://orcid.org/0000-0002-4035-4108. The author was engaged in conducting the experimental work.

Svetlana K. Kotovskaya, Ural Federal University named after the first President of Russia Boris N. Yeltsin

Candidate of Chemical Sciences (PhD), Senior Researcher of the Laboratory for the Synthesis of Biologically Active Compounds, Head of the Laboratory Pharmaceutical Substances Standardization of Innovative Centre for Chemical & Pharmaceutical Technologies, Ural Federal University Named after the First President of Russia B. N. Yeltsin, Ekaterinburg, Russia; e-mail: k.kotovskaya@urfu.ru; ORCID ID: https://orcid.org/0000-0002-3213-9838. The author advised on methods of synthesis, physicochemical analysis, and edited the text of the article.

Irina M. Sapozhnikova, Ural Federal University Named after the First President of Russia B. N. Yeltsin

Candidate of Chemical Sciences (PhD), Junior Researcher of the Laboratory for the Synthesis of Biologically Active Compounds, Ural Federal University Named after the First President of Russia B. N. Yeltsin, Ekaterinburg, Russia; e-mail: m.sapozhnikova@urfu.ru; ORCID ID: https://orcid.org/0000-0002-5193-9670. The author carried out and scaled up chemical synthesis.

Vladimir L. Rusinov, Ural Federal University Named after the First President of Russia B. N. Yeltsin

Doctor Habil. of Chemical Sciences (DSc), Professor, Corresponding Member of the Russian Academy of Sciences, Head of Organic & Biomolecular Chemistry Department, Head of the Laboratory of Organic Synthesis, Innovative Centre for Chemical & Pharmaceutical Technologies, Ural Federal University Named after the First President of Russia B. N. Yeltsin, Ekaterinburg, Russia; e-mail: vladimir-rusinov0103@yandex.ru; ORCID ID: https://orcid.org/0000-0002-1705-4078. The author advised on the research idea, analyzed the results and edited the text of the article.

Alexander A. Spasov, Volgograd State Medical University

Doctor Habil. of Medical Sciences (DSc), Professor, Corresponding Member of the Russian Academy of Sciences, Chairman of the Department of Pharmacology and Bioinformatics, Scientific advisor of Scientific Center for Innovative Medicines, Volgograd State Medical University, Volgograd, Russia; e-mail: aspasov@mail.ru; ORCID ID: https://orcid.org/0000-0002-7185-4826. The author advised on the research idea, the concept and design of the study, analyzed the results, and edited the text of the article.