Valerii Salnykov¹, Igor Belenichev² and Iryna Samura³

¹Department of Surgical and Propaedeutic Dentistry, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine.

²Department of Pharmacology and Medical Formulation with Course of Normal Physiology, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine.

³Department of Pharmacology and Medical Formulation with Course of Normal Physiology, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine.

Corresponding Author E-mail: irinasamura77@gmail.com

DOI : https://dx.doi.org/10.13005/bpj/2993

Abstract

Epidemiological studies in recent decades have revealed a significant increase in the number of patients with periodontal diseases leading to tooth loss. Modern realities require improvement of drug treatment of periodontitis. The antioxidant Selenase, selenium derivative, is an interesting treatment strategy for periodontitis. The study was carried out with the aim to evaluate the healing effectiveness of Selenase in rats with chronic generalized periodontitis (CGP) by its effect on markers of inflammation and cytoprotection. Experimental CGP was modulated in Wistar rats by a calcium-deficient diet with the inclusion of a prooxidant. Selenase (50 mcg/kg) and Mexidol (ethylmethylhydroxypyridine succinate, 250 mg/kg) were administered intragastrically for 30 days. Levels of IL-1β, HIF-1α, HSP70, and TNF-α were determined in the blood after treatment using the enzyme immunoassay method. Experimental CGP was characterized by the development of hyperemia, swelling, and bleeding of the gums; mobility of teeth; and gingival pockets up to 8 mm against the background of increased inflammatory markers (IL-1β, TNF-α), and molecular markers of cytoprotection (HIF-1α, HSP70) in the blood, indicating a homeostatic response of the periodontium in response to inflammation and subsequent hypoxia. Administration of Selenase to rats with CGP produced pronounced healing effects:  the reduction in the depth of periodontal pockets by 42.55 %, cessation of bleeding, and disappearance of swelling against the background of a decrease of inflammatory markers: IL-1β – by 44.6 %, and TNF-α – by 65.9 % (p < 0.05). HIF-1α increased by 36.8 %, and HSP70 – by 71.1 % compared to those of the control group, which was not given the treatment (p < 0.05). The results obtained suggest a significant influence of Selenase on HSP70-dependent mechanisms of endogenous cytoprotection. The results of the study found that the use of Selenase in experimental CGP is more effective than Mexidol.

Keywords

Antioxidants; Chronic generalized periodontitis; Inflammation; Mexidol; Selenase

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Copy the following to cite this article: Salnykov V, Belenichev I, Samura I. The Effect of Selenase on Inflammatory and Cytoprotective Markers in Experimental Chronic Generalized Periodontitis. Biomed Pharmacol J 2024;17(3).

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Introduction

Epidemiological studies conducted from 1990 to 2020 revealed a significant rise in patients with periodontal diseases leading to tooth loss. Thus, among the adult population of 17 countries, periodontitis was found in 62 %, and its severe form – in 23.6 %¹. As international clinical trials show, the current therapeutic strategy for the treatment of periodontitis does not provide significant success². Currently, medications obtained from various plant parts (bark, leaves, fruits, flowers, roots and rhizomes) are widely used in the treatment of periodontitis. The therapeutic effectiveness of essential oils that have anti-inflammatory, antibacterial, and wound-healing properties in inflammatory periodontal diseases, has been most studied^3,4. Precious metal nanomaterials are also used in the treatment of periodontitis^5,6.

Oxidative stress is of great interest as a promising target in the treatment of periodontitis. Bacteria in inflamed gum tissue and virulence factors entering the bloodstream cause an exaggerated inflammatory response of the body. IL-1β and TNF-α stimulating signaling pathways such as NF-κB (nuclear factor κ-light-chain enhancer of activated B cells), and mitogen-activated protein kinases, enhance the production of reactive oxygen species (ROS). Increased accumulation of ROS during periodontitis contributes to damage to DNA, proteins, and lipidss^7,8.

Herb extracts from medicinal plants with antioxidant activity such as bioflavonoids, carotenoids, organic acids, and polyphenols, are administered in periodontitis. However, practice shows that phytoantioxidants are not very effective due to low bioavailability and the peculiarity of the mechanism of antioxidant action⁹. Antioxidants such as melatonin, alpha-tocopherol, thiotriazoline, recombinant human superoxide dismutase (SOD), and mexidol have been shown to be effective in the treatment of periodontitis^10-14.

Selenium and selenium-containing compounds have interested researchers and dentists worldwide owing to their promising applications in periodontitis. Selenium-based drugs have been found to have antioxidant, anti-inflammatory, cytoprotective properties, and are low-toxic form of selenium^15,16.

Sodium selenite stimulates the conversion of methionine to cysteine, ​​and enhances glutathione synthesis. Due to its effect on cysteine-dependent domains, sodium selenite activates the expression of transcription factors such as p53 and NF-kB. Selenase exhibits cardio- and neuroprotective properties in myocardial infarction and cerebral ischemia. Selenase also has cardioprotective and neuroprotective action in myocardial infarction and cerebral ischemia^32,42.   All of the above predetermined the topicality and prospects of this study. Our scientific activities were aimed at studying the healing efficacy of Selenase (Sodium selenite), selenium-containing medication, under the conditions of modeling chronic generalized periodontitis CGP in rats by its effect on markers of inflammation and cytoprotection.

Materials and Methods

The study was conducted on 40 adult female Wistar rats (weight 180-230 g). All experiments were conducted in accordance with national and international guidelines for the humane treatment of laboratory animals. ^17,18. The Bioethics Commission of ZDMPU confirmed compliance with ethical standards (Protocol No. 3, dated March 22, 2021). Maintenance of animals during the acclimatization period, and during the experiment: rats were kept in accordance with the rules for the design, equipment and maintenance of vivaria.

Experimental Model

Experimental CGP was simulated by a calcium-deficient peroxide diet for 8 weeks. Drinking water was replaced with a 2 % aqueous solution of calcium complexon disodium salt of ethylenediaminetetraacetic acid (Trilon B). In parallel, rats were administered Delagil (Chloroquine phosphate, produced by ICN Hungary S.A.) at a daily dose of 30 mg/kg of body weight using a metal probe. Animals in the experiment received soft foods¹⁹ to reduce chewing function. Animals received the investigational drugs after CGP formation. The animals were divided into four groups, each with ten animals (n = 10):

Group 1 – healthy animals (intact), received normal saline solution (0.9 % NaCl) intragastrically for 30 days;

Group 2 (control) – after introduction of chloroquine phosphate and Trilon B for 8 weeks, received 0.9 % NaCl intragastrically for 30 days;

Group 3 – after introduction of chloroquine phosphate and Trilon B for 8 weeks, received Selenase 50 μg/kg (Mivolis, Germany) intragastrically using an atraumatic metal probe¹⁹ for 30 days;

Group 4 – after introduction of chloroquine phosphate and Trilon B for 8 weeks, received the reference medication Mexidol (Mexicor, PJSC “Technolog”, Ukraine) 250 mg/kg intragastrically daily¹⁴ for 30 days.

After 86 days of the study, blood was taken from the abdominal aorta after laparotomy in anesthetized rats. (Sodium thiopental, 40 mg/kg intraperitoneally) using a special syringe. The obtained blood was subjected to centrifugation to obtain serum. To do this, tubes with blood were placed in the rotor cells of Eppendorf 5804R centrifuge (Germany) and centrifugation was carried out at +4°C, at 1500 rpm, 20 min.

Levels of hypoxia inducible factor-1α (HIF-1α) in the serum were assessed using the solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) method. The ELISA Kit HIF-1 alpha ELISA kit ab275103 (Abcam Limited, UK) was used according to the instructions.  Levels of heat shock protein 70 (HSP₇₀) were calculated using the HSP₇₀ High-Sensitivity StressXpress ELISA Kit #MBS806878 (MyBioSource, Canada) according to the instructions supplied with the kits. IL-1β levels were calculated using the Rat Interleukin 1β test, IL-1β ELISA Kit #CSB-E08055r (CUSABIO TECHNOLOGY, USA) according to the instructions supplied with the kits.

The TNF-α content was determined with the Rat TNF alpha ELISA Kit #ab 108913 (Abcam, USA) in accordance with the instructions supplied with the kits. These analyses were conducted on a complete plate enzyme immunoassay analyzer (SIRIO-S, Seac, Italy).

Statistical Analysis

Normality of distribution was analyzed using the Kolmogorov-Smirnov (D) and Lilliefors tests, and the Shapiro-Wilk (W) test¹⁴. In addition, the magnitude of asymmetry and excess of the data distribution were assessed as a criterion of agreement. If it was impossible to reject the null hypothesis about statistically significant differences in the distribution of variables from normal, nonparametric methods of data analysis were used. In other cases, parametric methods were used. If there were variants sharply deviated from the mass of observations, based on the properties of the standard normal distribution, these were excluded from further analysis if their absolute value was greater or less than the critical value, calculated as the sum of the sample mean and the triple sample of mathematical expectation value. Based on the properties of the standard normal distribution, variants that sharply deviate from the mass of observations, which in absolute value were greater or less than the critical value, calculated as the sum of the sample mean and the triple value of the sample mathematical expectation, were excluded from further analysis. Analysis of variance (ANOVA) was used to calculate independent variables in more than two samples. Data were presented as the mean and standard error of representativeness of the sample mean. Data processing and statistical analysis of the results were carried out using the statistical package of the licensed program “STATISTICA® for Windows 6.0” (StatSoft Inc., No. AXXR712D833214FAN5), as well as “SPSS 16.0”, “Microsoft Excel 2003”. Statistical procedures and algorithms were performed in the form of specially written macros in the corresponding programs. Differences were judged as statistically significant if p-value was less than 0.05 for all analyses.

Results  

Data presented in tables 1 and 2 show that an 8-week administration of Chloroquine phosphate and Trilon B to rats led to typical symptoms of periodontitis: hyperemia, swelling, and bleeding of the gums; mobility of teeth; and the formation of periodontal pockets up to 8 mm. A pronounced healing effect characterized by a pronounced decrease in pocket depth to 4.6 mm; reduction of hyperemia, swelling and bleeding in rats with CGP taken Selenase. Rats with CGP receiving Mexidol had a less pronounced healing effect compared to the group receiving Selenase (Table 1). In animals of this group bleeding persisted when probing the periodontal pocket with a button probe; the depth of the periodontal pocket was about 6 mm; swelling of the gums and mobility of teeth remained, but were less compared to the control group.

Table 1: Concentration of IL-1β and TNF-α in the blood of rats with experimental CGP after administration of pharmacological medications

Markers studied	Group 1 (n=10)	Group 2  (n=10)	Group 3  (n = 10)	Group 4  (n = 10)
Periodontal pocket depth, mm	0	8.0 ± 0.431	4.6 ± 0.691*	6.0  ±  0.931*
IL-1β, ng/mL	0.13 ± 0.014	0.56 ± 0.1091	0.31 ± 0.028*1	0.397 ± 0.061
TNF-α,  ng/mL	0.112 ± 0.053	0.907 ± 0.1071	0.33 ± 0.02*1#	0.577 ± 0.03*1

Notes: * – in comparison with the control group (CGP) (p < 0.05);

¹  – in comparison with the intact group (p < 0.05);

^# – in comparison with the Mexidol group (p < 0.05)

Molecular studies of the peripheral blood of rats of the control group revealed pronounced elevation (several times) of concentration of proinflammatory cytokines such as IL-1β (p<0.05) and TNF-α (p<0.05) in plasma in comparison with the intact group.

The use of Selenase in rats with CGP contributed to a decrease in IL-1β by 44.6 % (p<0.05) and TNF-α – by 65.9 % (p < 0.05) in comparison with the control group. The use of Mexidol to rats with CGP contributed to the decrease in the levels of TNF-α by 36.3% (p < 0.05) compared to the control group without affecting the levels of IL-1β. As can be seen from the data in Table 1, Selenase was superior to Mexidol in reducing the levels of TNF-α. (p < 0.05).

The data characterizing the markers of endogenous cytoprotection HSP₇₀ and HIF-1α presented in Table 2 show an increase in the levels of HSP₇₀ in rats with CGP by 1.4 times compared to intact group, and the levels of HIF-1α – by twice compared to the intact group. Administration of Selenase led to the increase in the concentration of HIF-1α by 36.8 % (p < 0.05) compared to control group. Concentration of HSP₇₀ increased by 71.1 % compared to the control group, and by 138.0 % (p<0.05) compared to the intact group. These statistically significant results indicate a remarkable action of selenase on HSP₇₀-dependent mechanisms of endogenous cytoprotection. Administration of Mexidol contributed to the increase in HIF-1α by 12.9 % (p < 0.05) in comparison with the control group, without affecting the levels of HSP₇₀ in animals with CGP.

Table 2: Concentration of HIF-1α and HSP₇₀ in the blood of rats with experimental CGP after administration of pharmacological medications

Markers studied	Group 1 (n=10)	Group 2 (n=10)	Group 3 (n = 10)	Group 4 (n = 10)
HIF-1α, pg/ml	1874.1 ± 121.1	2761.2 ± 117.11	3778.3 ± 109.2*1#	3117.5 ± 112.3*1
HSP70, ng/ml	17.4 ± 0.82	24.2 ± 1.321	41.4  ± 4.22*1#	27.0 ± 4,11

Notes: * – compared to the control group (CGP) (p<0.05);

¹  – compared to the intact group (p<0.05);

^# – compared to the mexidol group (p <0.05)

Discussion

The results of the study indicate the development of a pronounced inflammatory process in the periodontium of animals with experimental CGP, which is also confirmed by our early research¹⁴.  The results of the enzyme immunoassay obtained in this work demonstrated changes in the levels of proinflammatory cytokines and cytoprotective factors during modeling of periodontitis, which are in line with ideas about the pathogenesis of this disease and do not contradict the data of other scientists^21,22.

Bacterial colonization of the surface of teeth and gum tissue leads to the initiation of inflammatory reactions that trigger molecular mechanisms in periodontal degradation and the development of periodontitis. Leukocytes release proinflammatory mediators that play an essential role in the progression of chronic periodontitis in response to bacterial colonization.

As a result of the described events, the production of both pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-12, and regulatory cytokines such as TNF-α, IL-4, IL-10 and IL-1RA increases. The increased production of chemokine interferon-inducible protein-10 (IP-10) is also noted.  Marked expression of pro-inflammatory cytokines against the background of increased levels of prostaglandin E₂, interferon-γ, and macrophage colony-stimulating factor enhance osteoclast function and activate bone resorption²³.

IL-1β promotes the destruction of periodontal tissue, bone resorption and induces the production of proteinases that destroy bone tissue. TNF-α and IL-1β can trigger molecular reactions leading to the activation of nitrosative and oxidative stress⁷. The bacterial cell and its components, IL-1β and TNF-α enhance molecular activation mechanisms of hypersensitive polymorphonucleocytes involved in the production of ROS²⁴. Another source of ROS formation during periodontitis is neutrophil NADPH oxidase, the activity of which increases during inflammation and correlates with an increase in the levels of proinflammatory cytokines²⁵. Pathological concentrations of IL-1β and TNF-α enhance the expression of inducible nitric oxide synthases (iNOS).  iNOS involved in the mechanisms of inflammation, the production of ROS, oxidative and nitrosative stress^26,27. ROS, free radicals and stable products of oxidative stress (malondialdehyde, 4-hydroxy-2-transnonenal, etc.) enhance the production of proinflammatory mediators, and gingival inflammation; reduce the expression of antioxidant enzymes, HIF-1α, and contribute to alveolar bone loss. Many recent studies confirm a close relationship between the severity of periodontitis and oxidative stress^28-30.

The increase in HSP₇₀ and HIF-1α in animals with CGP found in this study clearly corresponds to modern ideas about inflammatory periodontal diseases. IL-1, INF-γ and TNF-α produced in inflamed periodontal tissues function as triggers to induce HSP₇₀ production. Lipopolysaccharides also increase hyperthermia-induced HSP₇₀ levels in monocyte/macrophage cells. HSP₇₀ expression levels correlate with IL-1β levels in periodontitis. Increasing the production of HSP₇₀ provides an anti-inflammatory effect, protection of cells from oxidative stress, and damage to bone matrix proteins in the initial stages of periodontitis^7,31.

HSP₇₀ has antioxidant and anti-inflammatory effects, helps in early folding and refolding of proteins, protects the nucleus and lipid membrane from destruction, and prevents cell apoptosis³². HIF-1α, a major regulator of metabolism in periodontal tissue and alveolar bone, has critical functions in angiogenesis, erythropoiesis, energy metabolism, and cell fate determination during inflammation. However, the role of this factor in the regulation of cytoprotection/cytodestruction in chronic inflammation is not entirely clear and controversial^33,34. The results of this research and our previous study⁷ show a decrease in HIF-1α gene expression, and an increase in its expression in the protein level in experimental CGP. Apparently, changes in HIF-1α expression depend on both the duration and severity of the inflammatory response, and IL-1β and TNF-α modulate  its expression. In our case, a point at which the production of HIF-1α began to decrease, and the mechanisms of endogenous cytoprotection were disrupted, was reached. Many studies manifest both the stimulating effect of IL-1β and TNF-α on the synthesis of HIF-1α³⁵, and their inhibiting action on HIF-1α expression^36,37. The results obtained confirm the activation of endogenous cytoprotection mechanisms in response to inflammation in experimental CGP found in our earlier study¹⁴.

The above justifies the use of antioxidants in complex drug therapy of periodontitis. Studies have shown the role of selenium in the body’s antioxidant defense, and the significance of its deficiency in the development of periodontitis^38-40. The protective properties of selenase that we have identified in CGP can be explained from the point of view of both the antioxidant properties of selenium, and its ability to influence HSP₇₀-dependent mechanisms of endogenous cytoprotection. Thus, selenium can increase the expression of glutathione peroxidase 4 (GPR-4), inhibit the oxidation of membrane phospholipids, maintain the concentration of vitamin E, and regulate the thiol-disulfide balance^40-42.

Selenium influences inflammation indirectly by regulating the expression of cyclooxygenase and lipoxygenase through the mitogen-activated protein kinase (MAPK) pathway⁴³. Selenium can promote NF-κB entry into the nucleus and bind to areas of antioxidant/electrophilic regions of sensing elements (ARE/EpRE) to enhance the expression of antioxidant genes including GPx4, which reduces formation of pro-inflammatory metabolites of arachidonic acid⁴⁴. Selenase can increase the expression of the endogenous cytoprotection factor HSP₇₀ by increasing the levels of reduced thiols, especially glutathione^33,45. Selenium may influence cytoprotection mechanisms by regulating the levels of HIF-1α through VHL-1⁴⁶. Selenium may also prolong the lifetime of HIF-1α indirectly through HSP₇₀³⁴.

It was found that Mexidol did not significantly affect the levels of IL-1β in experimental CGP, but significantly lowered the expression of TNF-α, which may be due to the suppression of the expression of the succinate receptor SUCNR1/GPR91⁴⁷. The mechanisms of the antioxidant effect of Mexidol do not provide it with action on the expression of HSP₇₀ in animals with periodontitis. We identified a certain effect of Mexidol on the synthesis of HIF-1α in rats with CGP. Apparently, Mexidol modulates the level of HIF-1α through the succinate signaling system⁴⁸. Mexidol due to its antioxidant mechanisms impedes the oxidative modification of macromolecules, providing membrane-protective, antioxidant, and anti-inflammatory effects. Mexidol, due to the presence of a succinic acid residue in its structure, and inhibition of the expression of the succinate receptors SUCNR1/GPR91, reduces the levels of pro-inflammatory cytokines, such as TNF-1α⁴⁷.

Conclusion

Based on the results of the study, it can be concluded that:

Experimental CGP simulation in rats by 8-week administration of the prooxidant Delagil, and adding EDTA to water led to the development of typical symptoms of periodontitis: gum hyperemia, swelling, and bleeding; mobility of teeth; the formation of periodontal pockets up to 8 mm against the background of raised inflammatory markers IL-1β and TNF-α, and molecular markers HIF-1α and HSP₇₀, indicating the homeostatic response of the periodontium in response to inflammation and subsequent hypoxia. 

The course of treatment with a selenium derivative Selenase (50 mcg/kg) in a therapeutic regimen to rats with CGP produced pronounced healing effects:  the reduction in the depth of periodontal pockets to 4.6 mm; cessation of bleeding; and disappearance of swelling against the backdrop of declining levels of inflammatory markers: IL-1β – by 44.6 % (p < 0.05), and TNF-α – by 65.9 % (p < 0.05) and compared to the group of untreated animals.

The introduction of Selenase led to a rise in HIF-1α by 36.8 % (p < 0.05); an increase in HSP₇₀ by 71.1 % in comparison with untreated animals; and by 138 % (p < 0.05) in comparison with the intact animals. These data indicate a strong effect of Selenase on HSP₇₀-dependent mechanisms of endogenous cytoprotection.

Selenase was significantly superior to the reference medication Mexidol in experimental CGP by its action on the studied parameters.

The results obtained justify further study of Selenase as a promising treatment for CGP.

Acknowledgement

The authors would like to acknowledge the Zaporizhzhia State Medical and Pharmaceutical University for providing some facilities in carrying out the research.

Conflict of Interest

The author(s) do not have any conflict of interest.

Funding Source

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data Availability

The manuscript includes data obtained from the study.

Ethics Statement

Experiments and all manipulations with animals were carried out in accordance with the regulations on the use of animals in biomedical experiments (Strasbourg, 1986, as amended in 1998) and the European Convention for the Protection of Vertebrate Animals Used for Experimental and Scientific Purposes. The experimental research protocols and their results were approved by the decision of the ZSMPhU Bioethics Commission.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required

Authors’ Contribution

Valerii Salnykov ¹: collection and/or assembly of data, writing the article,

   Igor Belenichev²: research concept and design, data analysis and interpretation, writing the article, critical revision of the article

Iryna Samura³ ; data analysis and interpretation, writing the article, final approval of the article

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