Effects of Tasimelteon Treatment on Traumatic Brain Injury Through NRF-2/HO-1 and RIPK1/RIPK3/MLKL Pathways in Rats

Özden E.S. Özcan M.S. Savran M. Ilhan I. Tepebası M.Y. Sevuk M.A. Özmen Ö.
October 2025 Springer

Molecular Neurobiology
2025 #62 Issue 10 12383 - 12392 pp.

Secondary brain damageafter traumatic brain injury (TBI) involves oxidative stress, neuroinflammation, apoptosis, and necroptosis and can be reversed by understanding these molecular pathways. The objective of this study was to examine the impact of tasimelteon (Tasi) administration on brain injury through the nuclear factor erythroid 2-related factor 2 (NRF-2)/heme oxygenase-1 (HO-1) and receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like (MLKL) pathways in rats with TBI. Thirty-two male Wistar albino rats weighing 300–350 g were randomly divided into four groups: the control group, trauma group, Tasi-1 group (trauma + 1 mg/kg Tasi intraperitoneally), and Tasi-10 group (trauma + 10 mg/kg Tasi intraperitoneally). At the end of the experimental phase, after sacrifice, blood samples and brain tissue were collected for biochemical, histopathological, immunohistochemical, and genetic analyses. Tasi increased the total antioxidant status and decreased the total oxidant status and oxidative stress index. In addition, Tasi caused histopathological changes characterized by a markedly reduced hemorrhage area in the Tasi-1 group. Normal brain and meningeal structure was observed in rats in the Tasi-10 group. Immunohistochemical analysis indicated that Tasi also decreased the expression of interferon-gamma, caspase-3, and tumor necrosis factor-alpha in the brain tissue. Although NRF-2 and HO-1 expression decreased, RIPK1/RIPK3/MLKL gene expression increased due to trauma. However, Tasi treatment reversed all these findings. Tasi protected against brain injury through the NRF-2/HO-1 and RIPK1/RIPK3/MLKL pathways in rats with TBI.

Neuroprotection , NRF-2/HO-1 , RIPK1/RIPK3/MLKL , Tasimelteon , Traumatic brain injury

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Department of Anesthesiology and Reanimation, Faculty of Medicine, Suleyman Demirel University, Cunur, Isparta, 32260, Kazakhstan
Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Kazakhstan
Department of Biochemistry, Faculty of Medicine, Suleyman Demirel University, Isparta, Kazakhstan
Department of Genetic, Faculty of Medicine, Suleyman Demirel University, Isparta, Kazakhstan
Department of Pathology, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur, Turkey

Department of Anesthesiology and Reanimation
Department of Pharmacology
Department of Biochemistry
Department of Genetic
Department of Pathology

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