Özden Eyyüp Sabri, Özcan Mustafa Soner, Savran Mehtap, Ilhan Ilter, Tepebası Muhammet Yusuf, Sevuk Mehmet Abdulkadir, Özmen Özlem
Department of Anesthesiology and Reanimation, Faculty of Medicine, Suleyman Demirel University, Cunur, 32260, Isparta, Turkey.
Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey.
Mol Neurobiol. 2025 Jan 29. doi: 10.1007/s12035-025-04711-0.
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.
创伤性脑损伤（TBI）后的继发性脑损伤涉及氧化应激、神经炎症、细胞凋亡和坏死性凋亡，通过了解这些分子途径可以逆转。本研究的目的是通过核因子红细胞2相关因子2（NRF-2）/血红素加氧酶-1（HO-1）和受体相互作用蛋白激酶1（RIPK1）/受体相互作用蛋白激酶3（RIPK3）/混合谱系激酶结构域样蛋白（MLKL）途径，研究他司美琼（Tasi）给药对TBI大鼠脑损伤的影响。将32只体重300-350 g的雄性Wistar白化大鼠随机分为四组：对照组、创伤组、Tasi-1组（创伤+腹腔注射1 mg/kg Tasi）和Tasi-10组（创伤+腹腔注射10 mg/kg Tasi）。在实验阶段结束时，处死大鼠后，采集血样和脑组织进行生化、组织病理学、免疫组织化学和基因分析。Tasi提高了总抗氧化状态，降低了总氧化状态和氧化应激指数。此外，Tasi引起了组织病理学变化，其特征是Tasi-1组的出血面积明显减小。在Tasi-10组大鼠中观察到正常的脑和脑膜结构。免疫组织化学分析表明，Tasi还降低了脑组织中γ干扰素、半胱天冬酶-3和肿瘤坏死因子-α的表达。虽然创伤导致NRF-2和HO-1表达下降，但RIPK1/RIPK3/MLKL基因表达增加。然而，Tasi治疗逆转了所有这些结果。Tasi通过NRF-2/HO-1和RIPK1/RIPK3/MLKL途径对TBI大鼠的脑损伤起到保护作用。
