Inhibition of lipid peroxidation as a mechanism of neuroprotective action of melatonin in experimental acute cerebral ischemia

  • Michael Vladimirovich Osikov South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation; The State Budgetary Healthcare Institution Chelyabinsk Regional Clinical Hospital, 70 Vorovskiy str., Chelyabinsk, 454080, Russian Federation https://orcid.org/0000-0001-6487-9083
  • Alexey Viktorovich Shelomentsev South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation; State Budgetary Healthcare Institution Chelyabinsk Regional Clinical Therapeutic Hospital for War Veterans, 8 Medgorodok St., Chelyabinsk, 454080, Russian Federation https://orcid.org/0009-0002-1710-3922
  • Yuliya Sergeevna Shishkova South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation https://orcid.org/0000-0002-9221-7500
  • Margarita Sergeevna Boyko South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation https://orcid.org/0000-0002-4046-2424
  • Alexey Anatolyevich Fedosov Patrice Lumumba Peoples' Friendship University of Russia, 6 Miklukho-Maklaya str., Moscow, 117198, Russian Federation https://orcid.org/0000-0003-2224-5175
  • Anna Alekseevna Ageeva South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation https://orcid.org/0000-0002-3061-7621
DOI: https://doi.org/10.48612/pfiet/0031-2991.2025.04.123-132
Keywords: melatonin, citicoline, lipid peroxidation, acute experimental cerebral ischemia

Abstract

Due to the limited efficacy and safety of ischemic stroke treatment methods, melatonin (MT) in the original rectal suppositories, having pleiotropic properties, may be a promising neuroprotector.

The aim was to study the effect of MT in the composition of original rectal suppositories on the redox status in rat blood plasma in the dynamics of experimental acute cerebral ischemia (EACI).

The methodology. 40 male Wistar rats (220-240 g) were divided into 4 groups: I – false-operated, II, III, IV – EACI model (Chen S.T. et al.). Treatment (for 7 days): II – without treatment, III – rectal suppositories (2.5 mg MT / 100 mg) every 24 hours, IV – citicoline (100 mg / kg intravenously) every 24 hours. Neurological status (days 3 and 7, Garcia J.H. scale, Placing test), lipid peroxidation products (LPO) in plasma lipid extract (heptane and isopropanol phases) were evaluated. Results. With EACI, on days 3 and 7, there was a decrease in neurological parameters (Garcia J.H. scale and Placement test) and an increase in the level of LPO products in the plasma lipid extract. The use of rectal suppositories with MT significantly improved neurological status and decreased LPO indices, and correlation analysis confirmed the relationship between these processes. Citicoline also showed a positive effect, but its effect was less pronounced compared to MT and did not reach the control values.

Conclusion. The results obtained represent the neuroprotective effect of MT in the original rectal suppositories due to its systemic antioxidant effect, comparable to the currently used therapy, which suggests the expediency of their use in clinical practice.

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Author Biographies

Michael Vladimirovich Osikov, South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation; The State Budgetary Healthcare Institution Chelyabinsk Regional Clinical Hospital, 70 Vorovskiy str., Chelyabinsk, 454080, Russian Federation

Doctor of Medical Sciences, Professor, Head of the Department of Pathophysiology, South Ural State Medical University, Ministry of Health of the Russian Federation; Head of the Department of Scientific Work, Chelyabinsk Regional Clinical Hospital, Russia

Alexey Viktorovich Shelomentsev, South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation; State Budgetary Healthcare Institution Chelyabinsk Regional Clinical Therapeutic Hospital for War Veterans, 8 Medgorodok St., Chelyabinsk, 454080, Russian Federation

assistant of the Department of Pathophysiology at the South Ural State Medical University of the Ministry of Health of the Russian Federation; Neurologist at the Department of Therapeutic Specialists at the Chelyabinsk Regional Clinical Therapeutic Hospital for War Veterans, Russia

Yuliya Sergeevna Shishkova, South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation

Doctor of Medical Sciences, Professor, Professor of the Department of Microbiology, Virology and Immunology, South Ural State Medical University, Ministry of Health of the Russian Federation

Margarita Sergeevna Boyko, South Ural State Medical University, 64 Vorovskiy St., Chelyabinsk, 454092, Russian Federation

Candidate of Medical Sciences, Associate Professor of the Department of Pathophysiology, South Ural State Medical University, Ministry of Health of the Russian Federation

Alexey Anatolyevich Fedosov, Patrice Lumumba Peoples' Friendship University of Russia, 6 Miklukho-Maklaya str., Moscow, 117198, Russian Federation

Candidate of Medical Sciences, Associate Professor, Associate Professor of the Department of Histology, Cytology and Embryology of the Patrice Lumumba Peoples' Friendship University of Russia

References

1. Feigin V.L., Norrving M.B.B., Martins S., Sacco R.L., Hacke W. et al. World Stroke Organization (WSO): Global Stroke Fact Sheet 2022. International Journal of Stroke. 2022; 17(1): 18-29. doi: 10.1177/17474930211065917.
2. Ignatyeva V.I., Voznyuk I.A., Shamalov N.A., Reznik A.V., Vinitskiy A.A., Derkach E.V. Social and economic burden of stroke in Russian Federation. S.S. Korsakov Journal of Neurology and Psychiatry. 2023;123(8 2):5 15. (In Russian). https://doi.org/10.17116/jnevro20231230825
3. Cao Y., Yue X., Jia M., Wang J. Neuroinflammation and anti-inflammatory therapy for ischemic stroke. Heliyon. 2023; 9(7): e17972. doi: 10.1016/j.heliyon.2023.e17986..
4. Feske S.K., Steven K. Ischemic stroke. The American Journal of Medicine. 2021; 134(12): 1457-1464. doi: 10.1016/j.amjmed.2021.07.027.
5. Shen Z., Xiang M., Chen C., Ding F., Wang Y., Shang C. et al. Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke. Biomedicine & Pharmacotherapy. 2022; 151: 113125. doi: 10.1016/j.biopha.2022.113125.
6. Elsayed W.A., Mesallam E.H., El-Serafy D., Tamer. The relationship between oxidative stress and acute ischemic stroke severity and functional outcome. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 2020; 56: 5. doi: 10.1186/s41983-020-00206-y.
7. Paul S., Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Experimental Neurology. 2021; 335: 113518. doi: 10.1016/j.expneurol.2020.113518.
8. Barthels D., Das H. Current advances in ischemic stroke research and therapies. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2020; 1866(4): 165260. doi: 10.1016/j.bbadis.2018.09.012.
9. Ma N., Zhang J., Reiter R. J., Ma X. Melatonin mediates mucosal immune cells, microbial metabolism, and rhythm crosstalk: A therapeutic target to reduce intestinal inflammation. Medicinal Research Reviews. 2020; 40(2): 606-632. doi: 10.1002/med.21628.
10. Ma Q., Reiter R. J., Chen Y. Role of melatonin in controlling angiogenesis under physiological and pathological conditions. Angiogenesis. 2020; 23(2): 91-104. doi: 10.1007/s10456-019-09689-7.
11. Khedr E. M., Abbass M. A., Soliman R. K., Zaki A.F. Post-stroke dysphagia: Frequency, risk factors, and topographic representation: Hospital-based study. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 2021; 57: 23. doi: 10.1186/s41983-021-00281-9.
12. Brinkwirth S., Ayobami O., Eckmanns T., Markwart R. Hospital-acquired infections caused by enterococci: A systematic review and meta-analysis, WHO European Region, 1 January 2010 to 4 February 2020. Eurosurveillance. 2021; 26(45): 2001628. doi: 10.2807/1560-7917.ES.2021.26.45.2001628.
13. Jung Kim H., Hyun Park S. Sciatic nerve injection injury. Journal of International Medical Research. 2014; 42(4): 887-897. doi: 10.1177/0300060514531924.
14. Parliament, European & Council, European. 2010. DIRECTIVE 2010/63/EU on the protection of animals used for scientific purposes. EU Official Journal. L276.
15. Chen S. T., Hsu C. Y., Hogan E. L. Maricq H., Balentine J.D. A model of focal ischemic stroke in the rat: Reproducible extensive cortical infarction. Stroke. 1986; 17(4): 738-743. doi: 10.1161/01.str.17.4.738
16. Garcia J. H. Early reperfusion as a rationale form of therapy in ischemic stroke. Revista de Neurologia. 1995; 23(123): 1067-1073.
17. Schallert T., Woodlee M.T. Orienting and Placing. In: Whishaw I.Q., Kolb B., eds. The Behavior of the Laboratory Rat: A Handbook with Tests. online ed. New York: Oxford Academic; 2004: 129-140. doi.org/10.1093/acprof:oso/9780195162851.003.0012
18. Lvovskaya E.I., Volchegorsky I.A., Shemyakov S.E., Lifshits R.I. Spectrophotometric determination of the end products of lipid peroxidation. Voprosy Meditsinskoi Khimii. 1991; 37(4): 92-93. (In Russian).
19. Fomina M.A., Abalenikhina Ju.V., Fomina N.V., Terent'ev A.A. A method for complex assessment of the content of products of oxidative modification of proteins in tissues and biological fluids. Patent 2524667 C1, RF 2014. (In Russian).
20. Conte F., Buuringen N., Voermans N.C., Lefeber D.J. Galactose in human metabolism, glycosylation and congenital metabolic diseases: Time for a closer look. Biochimica et Biophysica Acta (BBA) - General Subjects. 2021; 1865(8): 129898. doi: 10.1016/j.bbagen.2021.129898.
21. Gao L., Peng L., Wang J., Zhang J.H., Xia Y. Mitochondrial stress: A key role of neuroinflammation in stroke. Journal of Neuroinflammation. 2024; 21(1): 44. doi: 10.1186/s12974-024-03033-7.
22. Qin C., Yang S., Chu Y. H., Zhang H., Pang X.W., Chen L. et al. Signaling pathways involved in ischemic stroke: Molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy. 2022; 7(1): 215. doi: 10.1038/s41392-022-01064-1.
23. Zetner D., Andersen L.P.H., Alder R., Jessen M.L., Tolstrup A., Rosenberg J. Pharmacokinetics and safety of intravenous, intravesical, rectal, transdermal, and vaginal melatonin in healthy female volunteers: A cross-over study. Pharmacology. 2021; 106(3-4): 169-176. doi: 10.1159/000510252.
24. Liu L., Labani N., Cecon E., Jockers R., Zawilska J.B. Melatonin target proteins: Too many or not enough? Frontiers in Endocrinology. 2019; 10: 791. doi: 10.3389/fendo.2019.00791.
25. Harpsøe N.G., Andersen L.P.H., Gögenur I., Rosenberg J. Clinical pharmacokinetics of melatonin: A systematic review. European Journal of Clinical Pharmacology. 2015; 71(8): 901-909. doi: 10.1007/s00228-015-1873-4.
26. Qin T., Feng D., Zhou B., Bai L., Yin Y. et al. Melatonin suppresses LPS-induced oxidative stress in dendritic cells for inflammatory regulation via the Nrf2/HO-1 axis. Antioxidants. 2022; 11(10): 2012. doi: 10.3390/antiox11102012.
27. Kurutas E.B. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: Current state. Nutrition Journal. 2015; 15: 71. doi: 10.1186/s12937-016-0186-5.
28. Zhang C., Ma Y., Zhao Y., Guo N., Han C., Wu Q. et al. Systematic review of melatonin in cerebral ischemia-reperfusion injury: Critical role and therapeutic opportunities. Frontiers in Pharmacology. 2024; 15: 1356112. doi: 10.3389/fphar.2024.1356112.
29. Sadanandan N., Cozene B., Cho J., Park Y.J., Saft M., Gonzales-Portillo B., Borlongan C.V. Melatonin — a potent therapeutic for stroke and stroke-related dementia. Antioxidants (Basel). 2020; 9(8): ID 672. doi: 10.3390/antiox9080672
Published
27-10-2025
How to Cite
Osikov M. V., Shelomentsev A. V., Shishkova Y. S., Boyko M. S., Fedosov A. A., Ageeva A. A. Inhibition of lipid peroxidation as a mechanism of neuroprotective action of melatonin in experimental acute cerebral ischemia // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2025. VOL. 69. № 4. PP. 123–132.
Issue
Vol. 69 No. 4 (2025)
Section
Original research