A.I. Burnasyan FMBC clinical bulletin. 2024 № 4
A.I. Abdullaeva, V.N. Olesova, D.Yu. Akopov, S.A. Abdullaev
Correction of Mitochondrial Dysfuction with Combined Use of the Drugs Metrogyl and
Aicar in an Experimental Model of Periodontitis
International Office, State Research Center – Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, Russiа
Contact person: Abdullaeva Albina Isupovna: albi.95@mail.ru
Abstract
Background: It is known that mitochondrial dysfunction is involved in the pathogenesis and progression of periodontitis, affecting oxidative stress and regulating inflammatory reactions. Therefore, in recent years, research on mitochondria-directed therapeutic approach to periodontal tissue diseases has been rapidly growing.
AIM: Evaluate the effect of the drugs Metrogyl and Aicar on structural and functional disorders in the mitochondria of periodontal tissues in an experimental model of periodontitis in laboratory rats.
Materials and methods: Male white Wistar rats weighing 221 ± 7.5 g at the age of 4 months were used in this work. The animals were divided by simple randomization into four groups, 10 animals in each: Group 1 – intact (control group); Group 2 – rats with modeled periodontitis; Group 3 – rats with modeled periodontitis and the use of Metrogyl; Group 4 – rats with modeled periodontitis and combined use of Metrogyl and Aicar. Experimental periodontitis (EP) in rats was modeled by the ligature method by suturing a polyfilament non-absorbable thread into the gum in the area of the lower incisors. The following molecular genetic and biochemical parameters were used: damage to nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), mtDNA copy number and the level of heteroplasmy, as well as the levels of malondialdehyde (MDA) and reduced glutathione (GSH).
Results: The data from this study showed that on the 14th day after ligation, animals in the periodontal tissue have an increased level of damage and mtDNA heteroplasmy, compared to the control group. The same animals showed a decrease in the GSH level, while the MDA level was increased compared to the control animals. In other groups of rats with EP, the modulation of these damages was assessed using Metrogyl, as well as the combined use of Metrogyl and Aicar. It was shown that for all the parameters studied, the combined use of Metrogyl and Aicar led to a more effective reduction in mitochondrial disorders, compared to the group of rats that received only Metrogyl.
Conclusions: The combined use of Metrogyl and Aicar drugs had a more effective effect on reducing mitochondrial dysfunction in periodontal tissue in rats with EP, in contrast to the group in which only Metrogyl was used. Thus, the use of traditional drugs in combination with mitochondria-targeted compounds that reduce oxidative stress may serve as a new therapeutic approach to various periodontal tissue diseases.
Keywords: periodontitis, mitochondrial dysfunction, Metrogyl, Aicar, mitochondrial DNA damage, malondialdehyde, reduced glutathione, rats
For citation: Abdullaeva AI, Olesova VN, Akopov DYu, Abdullaev SA. Correction of Mitochondrial Dysfuction with Combined Use of the Drugs Metrogyl and Aicar in an Experimental Model of Periodontitis A.I. Burnasyan Federal Medical Biophysical Center Clinical Bulletin. 2024.4:64-70. (In Russian) DOI: 10.33266/2782-6430-2024-4-64-70
REFERENCES
- Coll P.P., Lindsay A., Meng J., et al. The Prevention of Infections in Older Adults: Oral Health. J Am Geriatr Soc. 2020;68;2:411-416. doi: 10.1111/jgs.16154.
- Graziani F., Karapetsa D., Alonso B., Herrera D. Nonsurgical and Surgical Treatment of Periodontitis: How Many Options for One Disease? Periodontol 2000. 2017t;75;1:152-188. doi: 10.1111/prd.12201.
- Dong Z., Wu L., Hong H. Mitochondrial Dysfunction in the Pathogenesis and Treatment of Oral Inflammatory Diseases. Int J Mol Sci. 2023;24;15483. https://doi.org/10.3390/ijms242015483.
- Jiang W., Wang Y., Cao Z., et al. The Role of Mitochondrial Dysfunction in Periodontitis: From Mechanisms to Therapeutic Strategy. J Periodontal Res. 2023;58;5:853-863. doi: 10.1111/jre.13152.
- Deng Y., Xiao J., Ma L., et al. Mitochondrial Dysfunction in Periodontitis and Associated Systemic Diseases: Implications for Pathomechanisms and Therapeutic Strategies. Int J Mol Sci. 2024;25;2:1024. doi: 10.3390/ijms25021024.
- Abdullaev S., Gubina N., Bulanova T., Gaziev A. Assessment of Nuclear and Mitochondrial DNA, Expression of Mitochondria-Related Genes in Different Brain Regions in Rats after Whole-Body X-ray Irradiation. Int J Mol Sci. 2020;21;4:1196. doi: 10.3390/ijms21041196.
- Abdullaev S., Bulanova T., Timoshenko G., Gaziev A.I. Increase of mtDNA Number and its Mutant Copies in Rat Brain after Exposure to 150 MeV Protons. Mol Biol Rep. 2020;47;6:4815-4820. doi: 10.1007/s11033-020-05491-7.
- Abdullaev S.A., Glukhov S.I., Gaziev A.I. Radioprotective and Radiomitigative Effects of Melatonin in Tissues with Different Proliferative Activity. Antioxidants (Basel). 2021;10;12:1885. doi: 10.3390/antiox10121885.
- Abdullaev S.A., Glukhov, S.I., Gaziev A.I. Melatonin Reduces Radiation Damage to the Spleen and Increases Survival when Administered before and After the Exposure of Mice to X-ray Radiation. Biol Bull Russ Acad Sci. 2023;50:3069-3076. https://doi.org/10.1134/S1062359023110018.
- Abdullaev S., Minkabirova G., Karmanova E., et al. Metformin Prolongs Survival Rate in Mice and Causes Increased Excretion of Cell-Free DNA in the Urine of X-Irradiated Rats. Mutat Res Genet Toxicol Environ Mutagen. 2018;831:13-18. doi: 10.1016/j.mrgentox.2018.05.006.
- Tripathi V., Jaiswal P., Assaiya A., et al. Anti-Cancer Effects of 5-Aminoimidazole-4-Carboxamide-1-Beta-d-Ribofuranoside (Aicar) on Triple-Negative Breast Cancer (TNBC) Cells: Mitochondrial Modulation as an Underlying Mechanism. Curr Cancer Drug Targets. 2022;22;3:245-256. doi: 10.2174/1568009622666220207101212.
- Wu Y., Duan X., Gao Z., et al. Aicar Attenuates Postoperative Abdominal Adhesion Formation by Inhibiting Oxidative Stress and Promoting Mesothelial Cell Repair. PLoS One. 2022;17;9:e0272928. doi: 10.1371/journal.pone.0272928.
- Савкина А.А., Ленгерт Е.В., Ермаков А.В. и др. Влияние геля, содержащего микрокапсулы наночастиц серебра, загруженные метронидазолом, на состояние микроциркуляторного русла десны у животных с экспериментальным пародонтитом // Регионарное кровообращение и микроциркуляция. 2023. Т.2. №3. С. 78–85 [Savkina A.A., Lengert E.V., Ermakov A.V., et al. Effects of the Gel Containing Microcapsules with Silver Nanoparticles Loaded with Metronidazole on the State of the Gingival Microcirculation in Animals with Experimental Periodontitis. Regional Blood Circulation and Microcirculation. 2023;22;3:78–85 (In Russ.)]. doi:10.24884/1682-6655-2023-22-3-78-85.
- Ionel A., Lucaciu O., Moga M., et al. Periodontal Disease Induced in Wistar Rats – Experimental Study. HVM Bioflux. 2015;7;2:90-95.
- Zhu H., Chai Y., Dong D., et al. Aicar-Induced AMPK Activation Inhibits the Noncanonical Nf-kB Pathway to Attenuate Liver Injury and Fibrosis in BDL Rats. Can J Gastroenterol Hepatol. 2018;2018:6181432. doi: 10.1155/2018/6181432.
- Fu L.Y., Yang Y., Tian H., et al. Central Administration of AICAR Attenuates Hypertension Via AMPK/Nrf2 Pathway in the Hypothalamic Paraventricular Nucleus of Hypertensive Rats. Eur J Pharmacol. 2024;974:176373. doi: 10.1016/j.ejphar.2024.176373.
- Kawashima H., Ozawa Y., Toda E., et al. Neuroprotective and Vision-Protective Effect of Preserving ATP Levels by AMPK Activator. FASEB J. 2020;34;4:5016-5026. doi:10.1096/fj.201902387RR.
- Pyla R., Hartney T.J., Segar L. AICAR Promotes Endothelium-Independent Vasorelaxation by Activating AMP-Activated Protein Kinase Via Increased ZMP and Decreased ATP/ADP Ratio in Aortic Smooth Muscle. J. Basic. Clin. Physiol. Pharmacol. 2022;33;6:759-768. doi:10.1515/jbcpp-2021-0308.
- Sanli T., Steinberg G.R., Singh G., Tsakiridis T. AMP-Activated Protein Kinase (AMPK) Beyond Metabolism: a Novel Genomic Stress Sensor Participating in the DNA Damage Response Pathway. Cancer Biol. Ther. 2014;15;2:156-169. doi: 10.4161/cbt.26726.
- Hinkle J.S., Rivera C.N., Vaughan R.A. AICAR Stimulates Mitochondrial Biogenesis and BCAA Catabolic Enzyme Expression in C2C12 Myotubes. Biochimie. 2022;195:77-85. doi: 10.1016/j.biochi.2021.11.004.
- Dombi E., Mortiboys H., Poulton J. Modulating Mitophagy in Mitochondrial Disease. Curr. Med. Chem. 2018;25;40:5597-5612. doi: 10.2174/0929867324666170616101741.
- Yamano K., Matsuda N., Tanaka K. The Ubiquitin Signal and Autophagy: an Orchestrated Dance Leading to Mitochondrial Degradation. EMBO Rep. 2016;17;3:300-316. doi: 10.15252/embr.201541486.
- Ryytty S., Modi S.R., Naumenko N., et al. Varied Responses to a High m.3243a>g Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes. Cells. 2022;19;11:2593. doi: 10.3390/cells11162593.
Conflict of interest. The authors declare no conflict of interest.
Financing. The study had no sponsorship.
Contribution. Article was prepared with equal participation of the authors.
Article received: 13.09.2024. Accepted for publication: 11.10.2024