Effective wound healing agents based on N-alkenylimidazole zinc complexes derivatives: future prospects and opportunities

Svetlana A. Lebedeva; Pavel A. Galenko-Yaroshevsky (Jr.); Tatiana V. Fateeva; Sergey S. Pashin; Nataliya R. Pashina; Irina B. Nektarevskaya; Andrey V. Zadorozhniy; Olga V. Shelemekh; Marina Yu. Ravaeva; Elena N. Chuyan; Lusine O. Alukhanyan; Tereza R. Glechyan; Kerim Mutig; Maria Yu. Materenchuk

doi:10.18413/rrpharmacology.9.10047

Authors

Svetlana A. Lebedeva I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation https://orcid.org/0000-0003-0325-6397
Pavel A. Galenko-Yaroshevsky (Jr.) I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University) https://orcid.org/0000-0002-6279-0242
Tatiana V. Fateeva All-Russian Research Institute of Medicinal and Aromatic Plants https://orcid.org/0000-0002-8231-0621
Sergey S. Pashin I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation
Nataliya R. Pashina I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation https://orcid.org/0000-0003-1454-014X
Irina B. Nektarevskaya Rostov State Medical University https://orcid.org/0009-0009-6733-9977
Andrey V. Zadorozhniy Rostov State Medical University https://orcid.org/0000-0001-9552-8542
Olga V. Shelemekh Rostov State Medical University https://orcid.org/0000-0003-3488-9971
Marina Yu. Ravaeva V.I. Vernadsky Crimean Federal University https://orcid.org/0000-0002-6081-1628
Elena N. Chuyan V.I. Vernadsky Crimean Federal University https://orcid.org/0000-0001-6240-2732
Lusine O. Alukhanyan Kuban State Medical University
Tereza R. Glechyan Kuban State Medical University https://orcid.org/0009-0002-4983-2433
Kerim Mutig A.P. Nelyubin Institute of Pharmacy; I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation https://orcid.org/0000-0001-9006-5112
Maria Yu. Materenchuk I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation https://orcid.org/0000-0002-0711-4153

DOI:

https://doi.org/10.18413/rrpharmacology.9.10047

Abstract

Introduction: The therapeutic effect of commercially available domestic and foreign drugs for the treatment of various skin injuries is far from optimal. These drugs have no universal effects, but cause pronounced side reactions. There is a clear demand for development of innovative wound-healing drugs with antimicrobial properties, which increase the natural protective function of the skin. Pharmaceutical compounds with zinc nanoparticles have been increasingly recognized as a promising therapeutic direction. These drugs can easily penetrate into damaged tissues and stimulate metabolic processes. Zinc complexes with imidazole derivatives are of a particular interest. Imidazole acts as a structural fragment of many natural physiologically active compounds, thus providing targeted delivery of this essential trace element into the wound for inclusion in the multicascade mechanism of wound healing. The aim of the study: to provide experimental evidence for effects of recently developed zinc complexes with N-alkenylimidazole as wound healing agents.

Materials and Methods: Wound-healing effects of six 1% gels containing distinct N-alkenylimidazole zinc complexe derivatives based on the Na-carboxymethylcellulose (Na-CMC) were comparatively studied in 128 outbred white rats of both genders. The Na-CMC-based Zinc Sulfate 1% gel, Methyluracil and Solcoseryl served as reference drugs. After performing the local tolerance study of zinc complexes, linear and planar sterile wounds of comparable size were inflicted in anesthetized animals. The degree of healing was evaluated on the day 8 and day 28 after the treatment start by wound sizes and histological examination of inflammatory response, epithelization, granulation tissue, angiogenesis, and necrosis. The skin microcirculation system was evaluated using the laser Doppler Flowmetry (LDF), whereby the blood flow indicators were recorded 30 and 60 minutes after intraperitoneal administration of the trial compound. The antimicrobial activity of the zinc compounds was determined in vitro by means of their minimum inhibitory concentration suppressing the bacteria and fungi growth using the double serial dilution method in liquid culture media. The statistical data processing was performed using the Statistica 12 software package.

Results and Discussion: In the linear wound model, all animals treated with either of six experimental zinc compounds showed almost complete reduction in wound size (92-100%, p<0.05) on the day 8, significantly exceeding the wound healing in the control animals (reduction by 67-88 %, p<0.05) and effects of the reference drugs (reduction by 83-86%, p<0.05). In the planar wound model, the most significant wound healing effect was reached by using the gel containing N-isopropenylimidazole zinc diacetate (encoded as Pilim-1). The respective histological examination showed signs of complete epithelialization, absence of destructive changes in the epidermis, restoration of skin appendages and presence of mature granulation tissue. Intraperitoneal Pilim-1 administration at a dose of 20 mg/kg improved microcirculation in the rat skin, as judged by significant effects on perfusion and the amplitudes of the isolated rhythms of the LDF-gram. In addition, Pilim-1 exerted a moderate bacteriostatic and fungistatic activity, which was 2 times greater than the antimicrobial activity of Metronidazole.

Conclusion: Topical application of gels containing 1% N-alkenylimidazole zinc complex derivatives accelerates the healing of uninfected linear and planar wounds in comparison with the established reference drugs. The Pilim-1 zinc compound exhibited the most pronounced therapeutic effect. The observed in vitro antimicrobial action of Pilim-1 is of further interest for potential implications in treatment of infected skin wounds. The regenerative effect of this substance opens prospects for development of new drugs with improved wound healing properties.

Graphical Abstract

Keywords:

linear wound, N-alkenylimidazole derivatives, reparative regeneration, skin, planar wound, topical therapy, wound healing, zinc

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Author Contribution

Svetlana A. Lebedeva, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

Holder of an Advanced Doctorate (Doctor of Science) in Biological Sciences, Associate Professor, Professor of the Department of Pharmacology, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia; e-mail: lebedeva502@yandex.ru; ORCID ID https://orcid.org/0000-0003-0325-6397. The author’s contribution: concept development, formulation and development of the key aim and objectives; interpretations of the data obtained; writing a draft manuscript; being in charge of all aspects of the study, cohesion of its parts and the final version of the paper.

Pavel A. Galenko-Yaroshevsky (Jr.), I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)

Degree student of the Department of Pharmacology of A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia; Surgeon-Oncologist, Deputy Chief Physician for the Polyclinic section of work; e-mail: Pavelgalenko@bk.ru; ORCID ID https://orcid.org/0000-0002-6279-0242. The author’s contribution: collecting information and writing the article, participation in scientific design, being in charge of all aspects of the study.

Tatiana V. Fateeva, All-Russian Research Institute of Medicinal and Aromatic Plants

Head of the microbiological research laboratory, All-Russian Research Institute of Medicinal and Aromatic Plants, Moscow, Russia; e-mail: fateeva2151@mail.ru; ORCID ID https://orcid.org/0000-0002-8231-0621. The author’s contribution: interpretation of the data obtained and being in charge of all aspects of the study.

Sergey S. Pashin, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

Аssociate Professor of the Department of Human Anatomy and Histology,I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia; e-mail:pashinss@yandex.ru; ORCID ID https://orcid.org/0000-0001-9393-6278. The author’s contribution: interpretation of the data obtained and being in charge of all aspects of the study.

Nataliya R. Pashina, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

Associate Professor of the Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia; e-mail: pashina_n_r@staff.sechenov.ru; ORCID ID https://orcid.org/0000-0003-1454-014X. The author’s contribution:interpretation of the data obtained and being in charge of all aspects of the study.

Irina B. Nektarevskaya, Rostov State Medical University

Candidate of Medical Sciences (PhD in Medical Sciences), Associate Professor of the Department of Dentistry № 4, Rostov State Medical University, Rostov-on-Don, Russia; e-mail: nektir4546@mail.ru; ORCID ID https://orcid.org/0009-0009-6733-9977. The author’s contribution: analysis and interpretation of the data obtained.

Andrey V. Zadorozhniy, Rostov State Medical University

PhD in Medical Sciences, Associate Professor, Head of the Department of Dentistry No.4, Rostov State Medical University, Rostov-on-Don, Russia; e-mail: stomvr1@gmail.com; ORCID ID https://orcid.org/0000-0001-9552-8542. The author’s contribution: editing and preparing the article text, being in charge of the integrity of the article and its final version.

Olga V. Shelemekh, Rostov State Medical University

Postgraduate student of the Department of Dentistry № 4, Rostov State Medical University, Rostov-on-Don, Russia; e-mail: lioli777@yandex.ru; ORCID ID https://orcid.org/0000-0003-3488-9971. The author’s contribution: collecting data and drafting the article.

Marina Yu. Ravaeva, V.I. Vernadsky Crimean Federal University

PhD in Biological Sciences, Associate Professor, Department of Physiology of Humans and Animals and Biophysics, Faculty of Biology and Chemistry, V.I. Vernadsky Crimean Federal University, Simferopol, Russia; e-mail: ravaevam@yandex.ru; ORCID ID https://orcid.org/0000-0002-6081-1628. The author’s contribution: concept development, formulation and development of the key aim and objectives; interpretation of the data obtained.

Elena N. Chuyan, V.I. Vernadsky Crimean Federal University

Holder of an Advanced Doctorate (Doctor of Science) in Medical Sciences, Professor, Head of the Department of Physiology of Humans and Animals and Biophysics, Faculty of Biology and Chemistry, V.I. Vernadsky Crimean Federal University, Simferopol, Russia; e-mail: Elena-chuyan@rambler.ru; ORCID ID https://orcid.org/0000-0001-6240-2732. The author’s contribution: concept development, formulation and development of the key aim and objectives; interpretation of the data obtained; writing a draft manuscript.

Lusine O. Alukhanyan, Kuban State Medical University

PhD in Medical Sciences, Associate Professor, Department of Pediatric Dentistry, Orthodontics and Maxillofacial Surgery, Kuban State Medical University, Krasnodar, Russia; e-mail: LUS.0912@mail.ru; ORCID ID http://orсid.org/0009-0005-1752-2491. The author’s contribution: conducting research; analysis and interpretation of the data obtained; participation in research design.

Tereza R. Glechyan, Kuban State Medical University

PhD student, Department of Pharmacology, Kuban State Medical University, Krasnodar, Russia, e-mail: t_g91@mail.ru; ORCID ID https://orcid.org/0009-0002-4983-2433. The author’s contribution: collecting data and drafting the article.

Kerim Mutig, A.P. Nelyubin Institute of Pharmacy; I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

Dr. med., Professor of the Department of Pharmacology, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation ( Sechenov University), Moscow, Russia; Charité - Universitätsmedizin Berlin, Institut für Vegetative Physiologie, Berlin, Germany, e-mail: kmutig@googlemail.com; ORCID ID https://orcid.org/0000-0001-9006-5112. The author’s contribution: writing the manuscript and discussion of data.

Maria Yu. Materenchuk, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

5^th-year undergraduate student, Institute of Biodesign and Complex System Simulation, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia; e-mail: mariamatter231@gmail.com; ORCID ID https://orcid.org/0000-0002-0711-4153. The author’s contribution: development of the key aim and objectives; writing a draft manuscript; participation in research design; participation in preparing the final version of the paper in terms of visualization and data presentation.