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Year 2025, Volume: 52 Issue: 2, 299 - 307, 20.06.2025

Muhammet Yusuf Tepebaşı , Halil Aşçı , Özlem Özmen

https://doi.org/10.5798/dicletip.1723061

Abstract

References

  • 1. Maas AIR, Menon DK, Adelson PD, et al. Traumatic braininjury: integrated approaches to improve prevention,clinical care, and research. Lancet Neurol.2017;16(12):987-1048.
  • 2. Krishnamoorthy V, Mackensen GB, Gibbons EF, VavilalaMS. Cardiac dysfunction after neurologic injury: what dowe know and where are we going? Chest.2016;149(5):1325-31.
  • 3.Fesharaki-Zadeh A. Oxidative stress in traumatic braininjury. Int J Mol Sci. 2022;23(21):13000.
  • 4.Liu X, Zhang L, Cao Y, et al. Neuroinflammation oftraumatic brain injury: Roles of extracellular vesicles.Front Immunol. 2023;13:1088827.
  • 5.Liberale L, Ministrini S, Carbone F, Camici GG,Montecucco F. Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Res Cardiol. 2021;116(1):23.
  • 6.Maass DL, White J, Horton JW. IL-1β and IL-6 actsynergistically with TNF-α to alter cardiac contractilefunction after burn trauma. Shock. 2002;18(4):360-6.
  • 7.Caporizzo MA, Prosser BL. The microtubulecytoskeleton in cardiac mechanics and heart failure. NatRev Cardiol. 2022;19(6):364-78.
  • 8.Czabotar PE, Lessene G, Strasser A, Adams JM. Controlof apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol cell Biol.2014;15(1):49-63.
  • 9.Özmen Ö, Aşçı H, Savran M, Şahin M, Ozmen O.Amantadine preserve VCAM immunoexpression levels incardiac injury induced by brain trauma with its anti-inflammatory action and protective effect on themitochondrial membrane. Mehmet Akif Ersoy Univ J HealSci Inst. 2024;12(3):15-23.
  • 10.Ismail H, Shakkour Z, Tabet M, et al. Traumatic braininjury: oxidative stress and novel anti-oxidants such asmitoquinone and edaravone. Antioxidants.2020;9(10):943.
  • 11.Rodkin S, Nwosu C, Raevskaya M, et al. The Role ofHydrogen Sulfide in the Localization and Expression ofp53 and Cell Death in the Nervous Tissue in TraumaticBrain Injury and Axotomy. Int J Mol Sci.2023;24(21):15708.
  • 12.Vaziri H, Dessain SK, Eaton EN, et al. hSIR2SIRT1functions as an NAD-dependent p53 deacetylase. Cell.2001;107(2):149-59.
  • 13.Chen M, Liu J, Wu W, et al. SIRT1 restoresmitochondrial structure and function in rats by activatingSIRT3 after cerebral ischemia/reperfusion injury. CellBiol Toxicol. 2024;40(1):31.
  • 14.Cecon E, Oishi A, Jockers R. Melatonin receptors:molecular pharmacology and signalling in the context ofsystem bias. Br J Pharmacol. 2018;175(16):3263-80.
  • 15.Özden ES, Özcan MS, Savran M, et al. Effects ofTasimelteon Treatment on Traumatic Brain InjuryThrough NRF-2/HO-1 and RIPK1/RIPK3/MLKLPathways in Rats. Mol Neurobiol. Published online2025:1-10.
  • 16.Sieminski M, Reimus M, Kałas M, Stępniewska E.Antioxidant and Anti-Inflammatory Properties ofMelatonin in Secondary Traumatic Brain Injury.Antioxidants. 2024;14(1):25.
  • 17.Marmarou A, Foda MAAE, Van Den Brink W, et al. Anew model of diffuse brain injury in rats: Part I:Pathophysiology and biomechanics. J Neurosurg. 1994;80(2):291-300.
  • 18.Hardeland R. Investigational melatonin receptoragonists. Expert Opin Investig Drugs. 2010;19(6):747-64.
  • 19.Cuisinier A, Maufrais C, Payen JF, et al. Myocardialfunction at the early phase of traumatic brain injury: aprospective controlled study. Scand J Trauma ResuscEmerg Med. 2016;24:1-7.
  • 20. Hasanin A, Zakaria D, Allam A. Cardiac injury in severe head trauma: a review of literature. J NeurolNeuromedicine. 2016;1(8).
  • 21.Woodcock T, Morganti-Kossmann MC. The role ofmarkers of inflammation in traumatic brain injury. FrontNeurol. 2013;4:18.
  • 22.Kumar A, Loane DJ. Neuroinflammation aftertraumatic brain injury: opportunities for therapeuticintervention. Brain Behav Immun. 2012;26(8):1191-201.
  • 23.Yang Q, Zhou Y, Sun Y, et al. Will sirtuins be promisingtherapeutic targets for TBI and associatedneurodegenerative diseases? Front Neurosci.2020;14:791.
  • 24.Borutaite V, Toleikis A, Brown GC. In the eye of thestorm: mitochondrial damage during heart and brainischaemia. FEBS J. 2013;280(20):4999-5014.
  • 25.Plesnila N, Von Baumgarten L, Retiounskaia M, et al.Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-κB transcriptional activity.Cell Death Differ. 2007;14(8):1529-41.
  • 26.Sabet N, Soltani Z, Khaksari M. Multipotential andsystemic effects of traumatic brain injury. JNeuroimmunol. 2021;357:577619.
  • 27. Emir M, Ozisik K, Cagli K, et al. Effect of erythropoietinon bcl-2 gene expression in rat cardiac myocytes aftertraumatic brain injury. In: Transplantation Proceedings.Vol 36. Elsevier; 2004:2935-8.
  • 28.Wei G, Wang J, Wu Y, et al. Sirtuin 1 alleviatesneuroinflammation‐induced apoptosis after traumaticbrain injury. J Cell Mol Med. 2021;25(9):4478-86.
  • 29.Wei C, Wang J, Yu J, et al. Therapy of traumatic braininjury by modern agents and traditional Chinesemedicine. Chin Med. 2023;18(1):25.
  • 30.Jarrahi A, Braun M, Ahluwalia M, et al. Revisitingtraumatic brain injury: from molecular mechanisms totherapeutic interventions. Biomedicines.2020;8(10):389.
  • 31.Chen Z, Venkat P, Seyfried D, et al. Brain–heartinteraction: cardiac complications after stroke. Circ Res.2017;121(4):451-68.

The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/p53 Signaling, and Inflammatory Cytokine Pathways

Year 2025, Volume: 52 Issue: 2, 299 - 307, 20.06.2025

Muhammet Yusuf Tepebaşı , Halil Aşçı , Özlem Özmen

https://doi.org/10.5798/dicletip.1723061

Abstract

Aim: This study explores the cardioprotective effects of Tasimelteon (TASI), a selective melatonin receptor agonist, following traumatic brain injury (TBI). TBI triggers systemic inflammation, contributing to secondary cardiac injury and increased morbidity. While TASI shows neuroprotective properties, its potential to protect the heart after TBI remains unknown.
Methods: Four groups were created from thirty-two adult male rats: Trauma, Trauma + TASI (1 mg/kg), Trauma + TASI (10 mg/kg), and Sham. Heart tissue was taken for genetic, immunohistochemical, and histopathological examinations. Histopathology assessed hyperemia, hemorrhage, inflammation, and necrosis. Immunohistochemistry measured β-tubulin, IL-1, and IL-6 expression, while RT-qPCR analyzed SIRT1, p53, BAX, and BCL-2 mRNA levels.
Results: The Trauma group displayed symptoms of myocardial damage, such as hyperemia, bleeding, and disturbed cell architectures, but the Sham group's histopathological analysis indicated normal myocardial tissue. TASI treatments improved these findings, with TASI-10 being more effective. Immunohistochemistry showed minimal expression of β-tubulin, IL-1, and IL-6 in the Sham group, but significant upregulation in the Trauma group, indicating inflammation. Both TASI treatments reduced these markers, with TASI-10 showing the greatest reduction. According to gene expression study, trauma reduced anti-apoptotic genes (Sirt-1, Bcl-2) and elevated pro-apoptotic genes (Bax, p53). Gene expression was slightly restored by TASI-1, but TASI-10 significantly improved all four genes.
Conclusion: TASI treatment, particularly at a 10 mg dose, effectively ameliorates myocardial injury caused by Trauma, with improvements observed at the histological, molecular, and gene expression levels. This suggests that TASI may hold potential as a therapeutic agent for myocardial protection.

Keywords

Apoptosis Cardioprotective Inflammation Tasimelteon Traumatic Brain Injury

Supporting Institution

The research was funded under Project TSG-2024-9515 by Suleyman Demirel University’s Scientific Research Projects Coordination Unit.

References

  • 1. Maas AIR, Menon DK, Adelson PD, et al. Traumatic braininjury: integrated approaches to improve prevention,clinical care, and research. Lancet Neurol.2017;16(12):987-1048.
  • 2. Krishnamoorthy V, Mackensen GB, Gibbons EF, VavilalaMS. Cardiac dysfunction after neurologic injury: what dowe know and where are we going? Chest.2016;149(5):1325-31.
  • 3.Fesharaki-Zadeh A. Oxidative stress in traumatic braininjury. Int J Mol Sci. 2022;23(21):13000.
  • 4.Liu X, Zhang L, Cao Y, et al. Neuroinflammation oftraumatic brain injury: Roles of extracellular vesicles.Front Immunol. 2023;13:1088827.
  • 5.Liberale L, Ministrini S, Carbone F, Camici GG,Montecucco F. Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Res Cardiol. 2021;116(1):23.
  • 6.Maass DL, White J, Horton JW. IL-1β and IL-6 actsynergistically with TNF-α to alter cardiac contractilefunction after burn trauma. Shock. 2002;18(4):360-6.
  • 7.Caporizzo MA, Prosser BL. The microtubulecytoskeleton in cardiac mechanics and heart failure. NatRev Cardiol. 2022;19(6):364-78.
  • 8.Czabotar PE, Lessene G, Strasser A, Adams JM. Controlof apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol cell Biol.2014;15(1):49-63.
  • 9.Özmen Ö, Aşçı H, Savran M, Şahin M, Ozmen O.Amantadine preserve VCAM immunoexpression levels incardiac injury induced by brain trauma with its anti-inflammatory action and protective effect on themitochondrial membrane. Mehmet Akif Ersoy Univ J HealSci Inst. 2024;12(3):15-23.
  • 10.Ismail H, Shakkour Z, Tabet M, et al. Traumatic braininjury: oxidative stress and novel anti-oxidants such asmitoquinone and edaravone. Antioxidants.2020;9(10):943.
  • 11.Rodkin S, Nwosu C, Raevskaya M, et al. The Role ofHydrogen Sulfide in the Localization and Expression ofp53 and Cell Death in the Nervous Tissue in TraumaticBrain Injury and Axotomy. Int J Mol Sci.2023;24(21):15708.
  • 12.Vaziri H, Dessain SK, Eaton EN, et al. hSIR2SIRT1functions as an NAD-dependent p53 deacetylase. Cell.2001;107(2):149-59.
  • 13.Chen M, Liu J, Wu W, et al. SIRT1 restoresmitochondrial structure and function in rats by activatingSIRT3 after cerebral ischemia/reperfusion injury. CellBiol Toxicol. 2024;40(1):31.
  • 14.Cecon E, Oishi A, Jockers R. Melatonin receptors:molecular pharmacology and signalling in the context ofsystem bias. Br J Pharmacol. 2018;175(16):3263-80.
  • 15.Özden ES, Özcan MS, Savran M, et al. Effects ofTasimelteon Treatment on Traumatic Brain InjuryThrough NRF-2/HO-1 and RIPK1/RIPK3/MLKLPathways in Rats. Mol Neurobiol. Published online2025:1-10.
  • 16.Sieminski M, Reimus M, Kałas M, Stępniewska E.Antioxidant and Anti-Inflammatory Properties ofMelatonin in Secondary Traumatic Brain Injury.Antioxidants. 2024;14(1):25.
  • 17.Marmarou A, Foda MAAE, Van Den Brink W, et al. Anew model of diffuse brain injury in rats: Part I:Pathophysiology and biomechanics. J Neurosurg. 1994;80(2):291-300.
  • 18.Hardeland R. Investigational melatonin receptoragonists. Expert Opin Investig Drugs. 2010;19(6):747-64.
  • 19.Cuisinier A, Maufrais C, Payen JF, et al. Myocardialfunction at the early phase of traumatic brain injury: aprospective controlled study. Scand J Trauma ResuscEmerg Med. 2016;24:1-7.
  • 20. Hasanin A, Zakaria D, Allam A. Cardiac injury in severe head trauma: a review of literature. J NeurolNeuromedicine. 2016;1(8).
  • 21.Woodcock T, Morganti-Kossmann MC. The role ofmarkers of inflammation in traumatic brain injury. FrontNeurol. 2013;4:18.
  • 22.Kumar A, Loane DJ. Neuroinflammation aftertraumatic brain injury: opportunities for therapeuticintervention. Brain Behav Immun. 2012;26(8):1191-201.
  • 23.Yang Q, Zhou Y, Sun Y, et al. Will sirtuins be promisingtherapeutic targets for TBI and associatedneurodegenerative diseases? Front Neurosci.2020;14:791.
  • 24.Borutaite V, Toleikis A, Brown GC. In the eye of thestorm: mitochondrial damage during heart and brainischaemia. FEBS J. 2013;280(20):4999-5014.
  • 25.Plesnila N, Von Baumgarten L, Retiounskaia M, et al.Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-κB transcriptional activity.Cell Death Differ. 2007;14(8):1529-41.
  • 26.Sabet N, Soltani Z, Khaksari M. Multipotential andsystemic effects of traumatic brain injury. JNeuroimmunol. 2021;357:577619.
  • 27. Emir M, Ozisik K, Cagli K, et al. Effect of erythropoietinon bcl-2 gene expression in rat cardiac myocytes aftertraumatic brain injury. In: Transplantation Proceedings.Vol 36. Elsevier; 2004:2935-8.
  • 28.Wei G, Wang J, Wu Y, et al. Sirtuin 1 alleviatesneuroinflammation‐induced apoptosis after traumaticbrain injury. J Cell Mol Med. 2021;25(9):4478-86.
  • 29.Wei C, Wang J, Yu J, et al. Therapy of traumatic braininjury by modern agents and traditional Chinesemedicine. Chin Med. 2023;18(1):25.
  • 30.Jarrahi A, Braun M, Ahluwalia M, et al. Revisitingtraumatic brain injury: from molecular mechanisms totherapeutic interventions. Biomedicines.2020;8(10):389.
  • 31.Chen Z, Venkat P, Seyfried D, et al. Brain–heartinteraction: cardiac complications after stroke. Circ Res.2017;121(4):451-68.
There are 31 citations in total.

Details

Primary Language English
Subjects Medical Education, Health Services and Systems (Other)
Journal Section Original Articles
Authors

Muhammet Yusuf Tepebaşı

Halil Aşçı

Özlem Özmen

Publication Date June 20, 2025
Submission Date February 26, 2025
Acceptance Date June 5, 2025
Published in Issue Year 2025 Volume: 52 Issue: 2

Cite

APA Tepebaşı, M. Y., Aşçı, H., & Özmen, Ö. (2025). The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/p53 Signaling, and Inflammatory Cytokine Pathways. Dicle Medical Journal, 52(2), 299-307. https://doi.org/10.5798/dicletip.1723061
AMA Tepebaşı MY, Aşçı H, Özmen Ö. The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/p53 Signaling, and Inflammatory Cytokine Pathways. diclemedj. June 2025;52(2):299-307. doi:10.5798/dicletip.1723061
Chicago Tepebaşı, Muhammet Yusuf, Halil Aşçı, and Özlem Özmen. “The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/P53 Signaling, and Inflammatory Cytokine Pathways”. Dicle Medical Journal 52, no. 2 (June 2025): 299-307. https://doi.org/10.5798/dicletip.1723061.
EndNote Tepebaşı MY, Aşçı H, Özmen Ö (June 1, 2025) The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/p53 Signaling, and Inflammatory Cytokine Pathways. Dicle Medical Journal 52 2 299–307.
IEEE M. Y. Tepebaşı, H. Aşçı, and Ö. Özmen, “The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/p53 Signaling, and Inflammatory Cytokine Pathways”, diclemedj, vol. 52, no. 2, pp. 299–307, 2025, doi: 10.5798/dicletip.1723061.
ISNAD Tepebaşı, Muhammet Yusuf et al. “The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/P53 Signaling, and Inflammatory Cytokine Pathways”. Dicle Medical Journal 52/2 (June 2025), 299-307. https://doi.org/10.5798/dicletip.1723061.
JAMA Tepebaşı MY, Aşçı H, Özmen Ö. The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/p53 Signaling, and Inflammatory Cytokine Pathways. diclemedj. 2025;52:299–307.
MLA Tepebaşı, Muhammet Yusuf et al. “The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/P53 Signaling, and Inflammatory Cytokine Pathways”. Dicle Medical Journal, vol. 52, no. 2, 2025, pp. 299-07, doi:10.5798/dicletip.1723061.
Vancouver Tepebaşı MY, Aşçı H, Özmen Ö. The Role of Tasimelteon in Modulating Cardiac Injury Following Traumatic Brain Injury: A Focus on Bax/Bcl-2, SIRT1/p53 Signaling, and Inflammatory Cytokine Pathways. diclemedj. 2025;52(2):299-307.
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