Antioxidant Therapeutic Potential of S-Ketamin Against Cerebral Ischemia/Reperfusion Injury in Male Rats

Document Type : Original Article(s)

Authors

1 Assistant Professor, Department of Biology, Faculty of Science, Ilam University, Ilam, Iran

2 Pharmaceutics Research Center, Institute of Pharmaceutical Sciences, Kerman University of Medical Sciences, AND Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

3 Assistant Professor, Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

10.48305/jims.v43.i821.0749

Abstract

Background: Cerebral ischemia-reperfusion is a major cause of increased oxidative stress in the brain, which leads to cellular damage and impaired normal function. Antioxidant compounds can counteract the damaging mechanisms associated with ROS. This study investigated the effect of (S)-Ketamine on reducing oxidative stress and its associated damage in a rat model of cerebral ischemia-reperfusion.
Methods: 28 male Wistar rats weighing 250-300 grams were randomly divided into four groups: control, ischemia-saline, ischemia-low dose esketamine, and ischemia-high dose esketamine. Ischemia was induced by occluding both common carotid arteries (CCA) for 20 minutes. Esketamine was injected immediately after ischemia at doses of 0.1 and 0.25 mg per kg body weight. The activity of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), was assessed using ELISA, while lipid peroxidation was evaluated using the thiobarbituric acid method.
Findings: MDA levels, as an indicator of oxidative stress, were higher in the CA1 region of the hippocampus in ischemic rats, while in the (S)-Ketamine-treated groups, the activities of antioxidant enzymes SOD, CAT, and GPx significantly increased and MDA levels decreased, indicating an increase in antioxidant capacity and a decrease in oxidative stress caused by ischemia-reperfusion in these groups.
Conclusion: (S)-Ketamine may play a crucial role in mitigating cerebral ischemia-reperfusion injury by reducing oxidative stress and enhancing antioxidant enzyme activity.

Highlights

Sohaila Erfani: Google Scholar

Bagher Amirheidari: Google Scholar

Seyedeh Mahdieh Khoshnazar: Google Scholar

Keywords

Main Subjects

References

  1. Zhang M, Liu Q, Meng H, Duan H, Liu X, Wu J, et al. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9(1): 12.
  2. Khoshnazar M, Parvardeh S, Bigdeli MR. Alpha-pinene exerts neuroprotective effects via anti-inflammatory and anti-apoptotic mechanisms in a rat model of focal cerebral ischemia-reperfusion. J Stroke Cerebrovasc Dis 2020; 29(8): 104977.
  3. Yang Y, Li Z, Fan X, Jiang C, Wang J, Rastegar-Kashkooli Y, et al. Nanozymes: potential therapies for reactive oxygen species overproduction and inflammation in ischemic stroke and traumatic brain injury. ACS Nano 2024; 18(26): 16450-67.
  4. Khoshnazar M, Bigdeli MR, Parvardeh S, Pouriran R. Attenuating effect of α-pinene on neurobehavioural deficit, oxidative damage and inflammatory response following focal ischaemic stroke in rat. J Pharm Pharmacol 2019; 71(11): 1725-33.
  5. Orellana-Urzúa S, Briones-Valdivieso C, Chichiarelli S, Saso L, Rodrigo R. Potential role of natural antioxidants in countering reperfusion injury in acute myocardial infarction and ischemic stroke. Antioxidants (Basel) 2023; 12(9): 1760.
  6. Hassan HA, Ahmed HS, Hassan DF. Free radicals and oxidative stress: mechanisms and therapeutic targets. Hum Antibodies 2024; 32(4): 151-67.
  7. Hajam YA, Rani R, Ganie SY, Sheikh TA, Javaid D, Qadri SS, et al. Oxidative stress in human pathology and aging: molecular mechanisms and perspectives. Cells 2022; 11(3): 552.
  8. Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities and low-molecular-weight antioxidants. Arch Toxicol 2024; 98(5): 1323-67.
  9. An X, Yu W, Liu J, Tang D, Yang L, Chen X. Oxidative cell death in cancer: mechanisms and therapeutic opportunities. Cell Death Dis 2024; 15(8): 556.
  10. Behl T, Makkar R, Sehgal A, Singh S, Sharma N, Zengin G, et al. Current trends in neurodegeneration: cross talks between oxidative stress, cell death and inflammation. Int J Mol Sci 2021; 22(14): 7432.
  11. Shabani M, Erfani S, Abdolmaleki A, Afzali FE, Khoshnazar SM. Alpha-pinene modulates inflammatory response and protects against brain ischemia via inducible nitric oxide synthase-nuclear factor–kappa B-cyclooxygenase-2 pathway. Mol Biol Rep 2023; 50(8): 6505-16.
  12. Trimmel H, Helbok R, Staudinger T, Jaksch W, Messerer B, Schöchl H, et al. S (+)-ketamine: current trends in emergency and intensive care medicine. Wien Klin Wochenschr 2018; 130(9-10): 356-66.
  13. Xu W, Wang P, Wang D, Liu K, Zhang S, Zhao W, et al. S-ketamine alleviates carbon tetrachloride-induced hepatic injury and oxidative stress by targeting the Nrf2/HO-1 signaling pathway. Can J Physiol Pharmacol 2021; 99(12): 1308-15.
  14. Liu FF, Zhao S, Liu P, Huo SP. Influence of mTOR signaling pathway on ketamine-induced injuries in the hippocampal neurons of rats. Neurol Res 2019; 41(1): 77-86.
  15. Khoshnazar M, Parvardeh S, Bigdeli MR. Alpha-pinene exerts neuroprotective effects via anti-inflammatory and anti-apoptotic mechanisms in a rat model of focal cerebral ischemia-reperfusion. J Stroke Cerebrovasc Dis 2020; 29(8): 104977.
  16. Khoshnazar M, Bigdeli MR, Parvardeh S, Pouriran R. Attenuating effect of α-pinene on neurobehavioural deficit, oxidative damage and inflammatory response following focal ischaemic stroke in rat. J Pharm Pharmacol 2019; 71(11): 1725-33.
  17. Khoshnazar SM, Kazemi M, Amirheidari B. Neuroprotective effects of γ-terpinene in rats with acute cerebral ischemia: modulation of inflammation, apoptosis, and oxidation. Neurochem Res 2024; 49(7): 1863-78.
  18. Erfani S, Moghimi A, Aboutaleb N, Khaksari M. Protective effects of Nesfatin-1 peptide on cerebral ischemia reperfusion injury via inhibition of neuronal cell death and enhancement of antioxidant defenses. Metab Brain Dis 2019; 34: 79-85.
  19. Houldsworth A. Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants. Brain Commun 2024; 6(1): fcad356.
  20. Jurcau A, Ardelean AI. Oxidative stress in ischemia/reperfusion injuries following acute ischemic stroke. Biomedicines 2022; 10(3): 574.
  21. Pourheydar B, Shahi M, Farjah GH, Javanmard M, Karimipour M, Atabaki F. Evaluation of apoptosis in hippocampal cells of rat following intravenous injection of bone marrow stromal cells in ischemia-reperfusion model [in persian]. Studies in Medical Sciences 2014; 25(7): 586-97.
  22. Wu L, Xiong X, Wu X, Ye Y, Jian Z, Zhi Z, et al. Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front Mol Neurosci 2020;13: 28.
  23. Soares ROS, Losada DM, Jordani MC, Évora P, Castro-e-Silva O. Ischemia/reperfusion injury revisited: an overview of the latest pharmacological strategies. Int J Mol Sci 2019; 20(20): 5034.
  24. Yu X, Zhang H, Gan J. Low-dose sketamine promotes brain protection via the ERK/Nrf2 pathway in vascular dementia rats. 2023. Available from: https://assets-eu.researchsquare.com/files/rs-3599975/v1/8069c0f1-9c47-4034-be42-831d4155c241.pdf?c=1703152360
  25. Tang Y, Liu Y, Zhou H, Lu H, Zhang Y, Hua J, et al. Esketamine is neuroprotective against traumatic brain injury through its modulation of autophagy and oxidative stress via AMPK/mTOR-dependent TFEB nuclear translocation. Exp Neurol 2023; 366: 114436.
  26. Erfani S, Valadbeigi T, Aboutaleb N, Karimi N, Moghimi A, Khaksari M. Usnic acid improves memory impairment after cerebral ischemia/reperfusion injuries by anti-neuroinflammatory, anti-oxidant, and anti-apoptotic properties. Iran J Basic Med Sci 2020; 23(9): 1225-31.
  27. Aboutaleb N, Shamsaei N, Khaksari M, Erfani S, Rajabi H, Nikbakht F. Pre-ischemic exercise reduces apoptosis in hippocampal CA3 cells after cerebral ischemia by modulation of the Bax/Bcl-2 proteins ratio and prevention of caspase-3 activation. J Physiol Sci 2015; 65(5): 435-43.
  28. Abdel-Salam OM, Youness ER, Mohammed NA, Omara EA, Sleem AA. Effect of ketamine on oxidative stress following lipopolysaccharide administration. Comp Clin Pathol 2015; 24 :53-63.
  29. Shi J, Song S, Wang Y, Wu K, Liang G, Wang A, et al. Esketamine alleviates ferroptosis-mediated acute lung injury by modulating the HIF-1α/HO-1 pathway. Int Immunopharmacol 2024; 142(Pt A): 113065.
  30. Jurič A, Tariba Lovaković B, Zandona A, Rašić D, Češi M, Pizent A, et al. The effects of ketamine on viability, primary DNA damage and oxidative stress parameters in HepG2 and SH-SY5Y cells. Arh Hig Rada Toksikol 2023; 74(2): 106-14.
  31. Reus GZ, Carlessi AS, Titus SE, Abelaira HM, Ignácio ZM, da Luz JR, et al. A single dose of S-ketamine induces long-term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation. Dev Neurobiol 2015; 75(11): 1268-81.
  32. Bove M, Tucci P, Dimonte S, Trabace L, Schiavone S, Morgese MG. Postnatal antioxidant and anti-inflammatory treatments prevent early ketamine-induced cortical dysfunctions in adult mice. Front Neurosci 2020; 14: 590088.
Journal of Isfahan Medical School
Volume 43, Issue 821
1st Week, September
September and October 2025
Pages 749-758

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History

  • Receive Date: 25 December 2024
  • Accept Date: 25 August 2025

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