α-Tocopherol Inhibits Ferroptosis And Promotes Neurological Recovery In Spinal Cord Injury Through GPX4/ACSL4 Signaling Pathway

Objective: To observe the inhibitory effect of α-tocopherol(α-TOC)on ferroptosis in HT22 cells and the protective effect on motor function in mice after spinal cord injury and explore its molecular mechanism.Methods:The animal model of spinal cord injury(SCI)was established by modified Allen’s method.The mice were randomly divided into sham operation group and SCI group.After 1 week of grouping,the spinal cord tissues were extracted for metabolomics analysis to screen the metabolic pathways of target substances.Glutathione peroxidase 4inhibitor(RSL-3)was used to induce ferroptosis,and the levels of reactive oxygen species(ROS)and glutathione peroxidase 4(GPX4),cystine/glutamate transporter system light chain(x CT),and acyl-coa synthetase long chain family member 4(ACSL4)protein were measured after RSL-3 treatment and drug treatment.The protein levels of GPX4,x CT and ACSL4 in spinal cord tissue were also measured,and the changes of motor function after SCI were judged by behavioral scores.Results: Metabolomics analysis showed that the expression of 8metabolic pathways changed significantly after SCI,among which the glutathione metabolic pathway was significantly changed.α-TOC could inhibit the ferroptosis induced by RSL-3,reduce the generation of reactive oxygen species(P<0.05),and change the levels of related proteins.Histological α-TOC could improve the decrease of GPX4 and x CT and reduce the production of ACSL4 after SCI(P<0.01).The kinematic scores suggested that intraperitoneal injection of α-TOC could increase the BMS score and the Angle of inclined plate test after SCI in mice.Conclusion: α-TOC can inhibit the ROS production and ferroptosis process after SCI,thereby reducing the degeneration and death of neurons and promoting the survival and recovery of motor function of neurons.The results of the present study indicate that the neuroprotective effect ofα-TOC is due to the activation of GPX4 as well as the inhibition of oxidative stress response,thereby inhibiting the occurrence of ferroptosis.The results of this study provide new evidence for how α-TOC plays a key neuroprotective role in inhibiting the motor function destruction caused by ferroptosis,and provide new ideas for the clinical application of this drug in SCI in the future.