Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats

Valéria Tékus; Ádám István Horváth; Kata Csekő; Krisztina Szabadfi; Andrea Kovács-Valasek; Bese Dányádi; László Deres; Róbert Halmosi; Éva Sághy; Zoltán V Varga; Ernest Adeghate; Tamás Kőszegi; Péter Mátyus; Róbert Gábriel; Péter Ferdinandy; Erika Pintér; Zsuzsanna Helyes

doi:10.1016/j.biopha.2020.111105

Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats

Biomed Pharmacother. 2021 Feb:134:111105. doi: 10.1016/j.biopha.2020.111105. Epub 2020 Dec 15.

Authors

Valéria Tékus¹, Ádám István Horváth¹, Kata Csekő¹, Krisztina Szabadfi², Andrea Kovács-Valasek², Bese Dányádi³, László Deres⁴, Róbert Halmosi⁵, Éva Sághy⁶, Zoltán V Varga⁶, Ernest Adeghate⁷, Tamás Kőszegi⁸, Péter Mátyus⁹, Róbert Gábriel², Péter Ferdinandy¹⁰, Erika Pintér¹¹, Zsuzsanna Helyes¹²

Affiliations

¹ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12, H-7624, Pécs, Hungary; Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624, Pécs, Hungary.
² Department of Experimental Zoology and Neurobiology, University of Pécs, Faculty of Sciences, Ifjúság útja 6, H-7624, Pécs, Hungary; Retinal Neurobiology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624, Pécs, Hungary.
³ Department of Anatomy, University of Pécs, Medical School, Szigeti út 12, H-7624, Pécs, Hungary; Retinal Neurobiology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624, Pécs, Hungary.
⁴ Genomics and Experimental Cardiology Research Group, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624, Pécs, Hungary; HAS-UP Nuclear-Mitochondrial Interactions Research Group, H-1245, Budapest, Hungary; 1st Department of Medicine, Clinical Centre, University of Pécs, Medical School, Ifjúság útja 13, H-7624, Pécs, Hungary.
⁵ Genomics and Experimental Cardiology Research Group, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624, Pécs, Hungary; 1st Department of Medicine, Clinical Centre, University of Pécs, Medical School, Ifjúság útja 13, H-7624, Pécs, Hungary.
⁶ Department of Pharmacology and Pharmacotherapy, Semmelweis University, Faculty of Medicine, Nagyvárad tér 4, H-1089, Budapest, Hungary.
⁷ Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
⁸ Department of Laboratory Medicine, University of Pécs, Medical School, Ifjúság útja 13, H-7624, Pécs, Hungary.
⁹ Institute of Digital Health Sciences, Semmelweis University, Faculty of Health and Public Services, Ferenc tér 15, H-1094, Budapest, Hungary.
¹⁰ Department of Pharmacology and Pharmacotherapy, Semmelweis University, Faculty of Medicine, Nagyvárad tér 4, H-1089, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary.
¹¹ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12, H-7624, Pécs, Hungary; PharmInVivo Ltd., Szondi György u. 10, H-7629, Pécs, Hungary.
¹² Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12, H-7624, Pécs, Hungary; Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624, Pécs, Hungary; PharmInVivo Ltd., Szondi György u. 10, H-7629, Pécs, Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.

PMID: 33338750
DOI: 10.1016/j.biopha.2020.111105

Abstract

Diabetes mellitus is a common metabolic disease leading to hyperglycemia due to insufficient pancreatic insulin production or effect. Amine oxidase copper containing 3 (AOC3) is an enzyme that belongs to the semicarbazide-sensitive amine oxidase family, which may be a novel therapeutic target to treat diabetic complications. We aimed to explore the effects of AOC3 inhibition and to test the actions of our novel AOC3 inhibitor multi-target drug candidate, SZV 1287, compared to a selective reference compound, LJP 1207, in an 8-week long insulin-controlled streptozotocin (STZ)-induced (60 mg/kg i.p.) rat diabetes model. Both AOC3 inhibitors (20 mg/kg, daily s.c. injections) were protective against STZ-induced pancreatic beta cell damage determined by insulin immunohistochemistry and radioimmunoassay, neuropathic cold hypersensitivity measured by paw withdrawal latency decrease from 0 °C water, and retinal dysfunction detected by electroretinography. SZV 1287 showed greater inhibitory effects on beta cell damage, and reduced retinal apoptosis shown by histochemistry. Mechanical hypersensitivity measured by aesthesiometry, cardiac dysfunction and nitrosative stress determined by echocardiography and immunohistochemistry/Western blot, respectively, serum Na⁺, K⁺, fructosamine, and urine microalbumin, creatinine, total protein/creatinine ratio alterations did not develop in response to diabetes. None of these parameters were influenced by the treatments except for SZV 1287 reducing serum fructosamine and LJP 1207 increasing urine creatinine. We provide the first evidence for protective effects of AOC3 inhibition on STZ-induced pancreatic beta cell damage, neuropathic cold hypersensitivity and diabetic retinal dysfunction. Long-term treatment with our novel multi-target analgesic candidate, SZV 1287, is safe and effective also under diabetic conditions.

Keywords: Diabetic neuropathy; Diabetic retinopathy; LJP 1207; Semicarbazide-sensitive amine oxidase; Streptozotocin; Vascular adhesion protein 1.

MeSH terms

Amine Oxidase (Copper-Containing) / metabolism
Analgesics / pharmacology
Animals
Cell Adhesion Molecules / metabolism
Diabetes Complications / drug therapy*
Diabetes Complications / prevention & control
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / prevention & control
Diabetic Nephropathies / drug therapy
Diabetic Retinopathy / drug therapy
Humans
Hydrazines / pharmacology
Insulin / metabolism
Insulin-Secreting Cells
Male
Monoamine Oxidase Inhibitors / pharmacology*
Oxazoles / pharmacology*
Oximes / pharmacology*
Rats
Rats, Sprague-Dawley
Streptozocin / adverse effects

Substances

3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime
Analgesics
Cell Adhesion Molecules
Hydrazines
Insulin
Monoamine Oxidase Inhibitors
N'-(2-phenylallyl)hydrazine
Oxazoles
Oximes
Streptozocin
Amine Oxidase (Copper-Containing)
vascular adhesion protein-1, rat