Tasimelteon Attenuates Lung Injury Following Traumatic Brain Injury: Histopathological and Immunohistochemical Evidence in a Rat Model

Abstract

Objective Traumatic brain injury (TBI) frequently causes secondary damage in distant organs, particularly the lungs, contributing to poor clinical outcomes. We aimed to assess whether tasimelteon (TASI), a melatonin receptor agonist, could mitigate pulmonary injury resulting from TBI in a rat model. Material and Method Forty male Wistar albino rats were randomly allocated to four distinct experimental groups: control, trauma (TRA), TRA + TASI 1mg/kg, and TRA + TASI 10mg/ kg. TBI was induced via Marmarou’s weight-drop model. Lung tissue samples were evaluated 24 hours after TBI via histopathological and immunohistochemical analyses targeting B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and Tumor Necrosis Factor-alpha (TNF-α). Results TBI induced significant alveolar damage, hyperemia, edema, and elevated Bax and TNF-α expression while reducing anti-apoptotic Bcl-2 levels. TASI, particularly at 10 mg/kg, significantly reversed these histological and molecular alterations (p < 0.05). Conclusion TASI provides dose-dependent protection against TBI-induced lung injury through modulation of apoptotic and inflammatory pathways. Its melatoninergic actions may represent a promising therapeutic option for managing multi-organ complications post-TBI.

Keywords

• Tasimelteon
• traumatic brain injury
• lung injury
• melatonin receptor agonist
• apoptosis
• inflammation

Supporting Institution

This work was supported by the Scientific Research Coordination Unit of Suleyman Demirel University [TSG-2024-9515].

Project Number

TSG-2024-9515

Ethical Statement

Ethical clearance for the experiment was obtained from the Suleyman Demirel University Local Animal Experiments Ethics Committee (Ethic No. 15.05.2025/05/513).

References

1. 1. Kumar A, Loane DJ. Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun. 2012;26(8):1191-1201. doi:10.1016/j.bbi.2012.06.008.
2. 2. Mascia L. Acute lung injury in patients with severe brain injury: a double-hit model. Neurocrit Care. 2009;11(3):417-426. doi:10.1007/s12028-009-9242-8.
3. 3. Wang L, Chen X, Wang Y. Neural-respiratory inflammasome axis in traumatic brain injury. Neuroimmunol Neuroinflamm. 2020;7:44. doi:10.20517/2347-8659.2020.44.
4. 4. Zhang Y, Li X, Du C, Huang T, Tang H. Immune modulation after traumatic brain injury. Front Med (Lausanne). 2022;9:995044. doi:10.3389/fmed. 2022.995044.
5. 5. Kim HJ, Lee H, Lee JH, Kim Y, Min JJ, Choi Y. Brain-lung interaction: a vicious cycle in traumatic brain injury. Acute Crit Care. 2020;35(4):255-263. doi:10.4266/acc.2020.00552.
6. 6. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jiménez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61(3):253-278. doi:10.1111/ jpi.12360.
7. 7. Lockley SW, Dressman MA, Licamele L, Xiao C, Fisher DM, Flynn-Evans EE, et al. Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials. Lancet. 2015;386(10005):1754-1764. doi:10.1016/ S0140-6736(15)60031-9.
8. 8. Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI. Therapeutic application of melatonin in mild cognitive impairment. Am J Neurodegener Dis. 2012;1(3):280-291.

9. 9. Andersen LPH, Gögenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clin Drug Investig. 2016;36(3):169- 175. doi:10.1007/s40261-015-0368-5.
10. 10. Özden ES, Özcan MS, Savran M, Ilhan I, Tepebaşı MY, Sevuk MA, et al. Effects of tasimelteon treatment on traumatic brain injury through NRF-2/HO-1 and RIPK1/RIPK3/MLKL pathways in rats. Mol Neurobiol. 2025 [Epub ahead of print]. doi:10.1007/ s12035-025-04711-0.
11. 11. Cikriklar HI, Uysal O, Ekici MA, Özbek Z, Turgut Cosan D, Yücel M, et al. Effectiveness of GFAP in determining neuronal damage in rats with induced head trauma. Turk Neurosurg. 2016;26(6):878-889. doi:10.5137/1019-5149.JTN.13946-15.2.
12. 12. Özmen O, Milletsever A, Tasan Ş, Selçuk E, Savran M. The effects of cannabidiol against methotrexate-induced lung damage. Basic Clin Pharmacol Toxicol. 2024;134(5):695-703. doi:10.1111/bcpt.13992.
13. 13. Pan F, Zhou Y, Liu J, Xu Y, Peng J. Lung and peripheral organ injuries induced by traumatic brain injury. SSRN [Preprint] [Internet]. 2024 [cited 2025 Aug 1]. Available from: https://ssrn. com/abstract=4886553.
14. 14. Ziaka M, Exadaktylos A. Brain-lung interactions and mechanical ventilation in patients with isolated brain injury. Crit Care. 2021;25(1):358. doi:10.1186/s13054-021-03778-0.
15. 15. Wang Y, Zhang L, Chen W, et al. Mitochondrial oxidant generation initiates BAX- or BAK-dependent alveolar epithelial cell death, which contributes to hyperoxia-induced lung injury. Am J Respir Cell Mol Biol. 2011;45(4):723-730. doi:10.1165/rcmb. 2010-0457OC.
16. 16. Dong H, Zhang H, Cai L, Ye Q, Wang H, Liu B, et al. Inflammatory signaling induces mitochondrial dysfunction and neuronal death in traumatic brain injury via downregulation of OXPHOS genes. Biochem Genet. 2024 [Epub ahead of print]. doi:10.1007/s10528-024-10980-6.
17. 17. Caceres E, Olivella JC, Di Napoli M, Raihane AS, Divani AA. Immune response in traumatic brain injury. Curr Neurol Neuros- ci Rep. 2024;24:593-609. doi:10.1007/s11910-024-01382-7.
18. 18. Hardeland R. Melatonin: signaling mechanisms of a pleiotropic agent. Biofactors. 2009;35(2):183-192. doi:10.1002/biof. 23.
19. 19. Xie L, Li S, Fan Y, Qi M, Li Z. Melatonin alleviates traumatic brain injury-induced anxiety-like behaviors in rats: roles of the protein kinase A/cAMP-response element-binding signaling pathway. Exp Ther Med. 2022;23(4):248. doi:10.3892/ etm.2022.11173.
20. 20. Peng Y, Jin J, Fan L, Xu H, He P, Li J, et al. Melatonin attenuates early brain injury via the melatonin receptor/Sirt1/NF-OE∫B signaling pathway following subarachnoid hemorrhage in mice. Neurochem Res. 2016;41(5):1106-1117. doi:10.1007/s11064- 016-1867-2.
21. 21. Mohseni M, Mihandoost E, Shirazi A, Sepehrizadeh Z, Tavakkoly Bazzaz J, Ghazi-Khansari M. Melatonin may play a role in modulation of Bax and Bcl-2 expression levels to protect rat peripheral blood lymphocytes from gamma irradiation-induced apoptosis. Mutat Res. 2012;738-739:19-27. doi:10.1016/j. mrfmmm.2012.08.006.
22. 22. Reiter RJ, Sharma R, Rosales-Corral S, Tan DX, Jou MJ, Galano A, et al. Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas. Cell Mol Life Sci. 2020;77(9):1889- 1903. doi:10.1007/s00018-019-03393-6.
23. 23. Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003;4(7):552-565. doi:10.1038/nrm1150.
24. 24. Zhang Y, Li X, Grailer JJ, Wang N, Wang M, Yao J, et al. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome. Cell Mol Immunol. 2016;13(6):789-800. doi:10.1038/cmi.2015.87.
25. 25. Cederroth CR, Canlon B. Medicine in the fourth dimension. Cell Metab. 2019;30(2):238-250. doi:10.1016/j.cmet.2019.06.019