Abstract：
Spinal cord injury (SCI) is a type of central nervous system (CNS) injury in which ferroptosis is becoming a promising target for treatment. Alpha-tocopherol (Vitamin E, Vit E) is a compound with anti-ferroptosis activity. The mechanism of alpha-tocopherol in regulating ferroptosis after SCI has not been deeply studied. In this study, rats with SCI were treated by Alpha-tocopherol based on bioinformatic analysis and molecular docking prediction. Behavioral tests and histological findings showed that Alpha-tocopherol promoted neural function recovery and tissue repairment in rats with SCI. Subsequently, regulatory effects of Alpha-tocopherol on Alox15 and ferroptosis were detected and then localized by immunofluorescence. In vitro, alpha-tocopherol improved the ROS accumulation, iron overload, lipid peroxidation and mitochondrial dysfunction. The effects of Alpha-tocopherol on the expression of Alox15, Ptgs2 and 4Hne were validated in vitro. Finally, the inhibitory effects of Alpha-tocopherol on Alox15 and ferroptosis were weakened by the mutation of 87th residue of Alox15. In summary, alpha-tocopherol could alleviate SCI-induced ferroptosis by downregulating Alox15 to promote neural function recovery in rats with SCI. Findings in this study could help further our understanding on SCI-induced ferroptosis and provide a novel insight for treating SCI.
摘要：
脊髓损伤（SCI）是一种中枢神经系统（CNS）损伤，其中铁性凋亡正在成为有希望的治疗目标。α-生育酚（维生素E，VitE）是具有抗铁死亡活性的化合物。α-生育酚调节SCI后铁凋亡的机制尚未深入研究。在这项研究中,根据生物信息学分析和分子对接预测，对SCI大鼠进行α-生育酚治疗。行为测试和组织学发现表明，α-生育酚促进SCI大鼠的神经功能恢复和组织修复。随后，检测α-生育酚对Alox15和铁凋亡的调节作用，然后通过免疫荧光进行定位。体外，α-生育酚改善了ROS的积累，铁过载，脂质过氧化和线粒体功能障碍。体外验证了α-生育酚对Alox15、Ptgs2和4Hne表达的影响。最后,Alox15第87残基的突变削弱了α-生育酚对Alox15和铁凋亡的抑制作用。总之,α-生育酚可以通过下调Alox15来减轻SCI诱导的大鼠铁凋亡，从而促进SCI大鼠的神经功能恢复。这项研究的发现可以帮助我们进一步了解SCI诱导的铁性凋亡，并为治疗SCI提供新的见解。
