Abstract：Objective To explore the mechanism of propofol in regulating ferroptosis through SIRT1/Nrf2 pathway in rats with cerebral ischemia/reperfusion (I/R) injury. Methods The rat brain I/R model was constructed and the mouse hippocampal neuron HT22 cells were treated with oxygen and glucose deprivation/reoxygenation (OGD/R) in vitro and pre-treated with propofol. Cerebral infarct volume was analyzed by TTC staining. Western blot was carried out to determine related protein levels of SIRT1/Nrf2 signaling and ferroptosis in the brain tissue of rats. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and Fe2+ levels in the brain tissue of rats were detected by corresponding kits. SIRT1 was silenced in rats and HT22 cells, and SIRT1 and Nrf2 were silenced simultaneously in HT22 cells. The changes of SIRT1/Nrf2 signaling related proteins and ferroptosis in rat brain tissue were detected. HT22 cells were treated with autophagy inhibitor 3-MA, and the expression of autophagy-related proteins and ferroptosis changes were detected. Results The cerebral infarct volume of the I/R group was higher than those of the Sham group, and the propofol group were lower than those of the I/R group. The protein expressions of SIRT1, Nrf2, HO-1 and NQO1 in brain tissue of rats in I/R group were higher than those in Sham group, and those in propofol group were lower than I/R group. Compared with Sham group, ROS, MDA, Fe2+ and Ptgs2 levels in the brain tissue of rats in I/R group were increased, and SOD and GPX-4 levels were decreased, and propofol reversed these results (P<0.01). Compared with the propofol group, SIRT1 silencing increased ROS, MDA and Fe2+ levels and decreased SOD level in the brain tissue of I/R rats and HT22 cells after ODG/R, and overexpression of Nrf2 reversed these results. After ODG/R, the ratio of LC3Ⅱ/Ⅰ were increased in HT22 cells, and propofol down-regulated these results. The silence of SIRT1 up-regulated the ratio of LC3Ⅱ/Ⅰ, and the autophagy inhibitor treatment down-regulated these results, reduced the levels of ROS, MDA and Fe2+, and increased the level of SOD. Conclusion Propofol inhibits autophagy and reduces ferroptosis through activation of SIRT1/Nrf2 pathway to protect brain I/R injury in rats.
[1] Parvardeh S, Sheikholeslami M A, Ghafghazi S, et al.Minocycline Improves Memory by Enhancing Hippocampal Synaptic Plasticity and Restoring Antioxidant Enzyme Activity in a Rat Model of Cerebral Ischemia-Reperfusion[J]. Basic Clin Neurosci, 2022, 13(2): 225-235. [2] Xu F, Ma R, Zhang G, et al.Estrogen and propofol combination therapy inhibits endoplasmic reticulum stress and remarkably attenuates cerebral ischemia-reperfusion injury and OGD injury in hippocampus[J]. Biomed Pharmacother, 2018, 108: 1596-1606. [3] Chen X, Li J, Kang R, et al.Ferroptosis: machinery and regulation[J]. Autophagy, 2021, 17(9): 2054-2081. [4] Xie J, Zhang T, Li P, et al.Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis[J]. Drug Des Devel Ther, 2022, 16: 3071-3085. [5] Dong H, Qiang Z, Chai D, et al.Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1[J]. Aging, 2020, 12(13): 12943-12959. [6] Zhao Z, Wu J, Xu H, et al.XJB-5-131 inhibited ferroptosis in tubular epithelial cells after ischemia-reperfusion injury[J]. Cell Death Dis, 2020, 11(8): 629. [7] Tuo Q Z, Liu Y, Xiang Z, et al.Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion[J]. Signal Transduct Target Ther, 2022, 7(1): 59. [8] Chen L, Li S, Zhu J, et al.Mangiferin prevents myocardial infarction-induced apoptosis and heart failure in mice by activating the Sirt1/FoxO3a pathway[J]. J Cell Mol Med, 2021, 25(6): 2944-2955. [9] Manjula R, Anuja K, Alcain FJ.SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases[J]. Front Pharmacol, 2020, 11: 585821. [10] Li S, Lei Z, Yang X, et al.Corrigendum: Propofol Protects Myocardium From Ischemia/Reperfusion Injury by Inhibiting Ferroptosis Through the AKT/p53 Signaling Pathway[J]. Front Pharmacol, 2022, 13: 910421. [11] Mei Z, Du L, Liu X, et al.Diosmetin alleviated cerebral ischemia/reperfusion injury in vivo and in vitro by inhibiting oxidative stress via the SIRT1/Nrf2 signaling pathway[J]. Food Funct, 2022, 13(1): 198-212. [12] Zeng Y, Cao G, Lin L, et al.Resveratrol Attenuates Sepsis-Induced Cardiomyopathy in Rats through Anti-Ferroptosis via the Sirt1/Nrf2 Pathway[J]. J Invest Surg, 2023, 36(1): 2157521. [13] Liu H, Zhao Z, Wu T, et al.Inhibition of autophagy-dependent pyroptosis attenuates cerebral ischaemia/reperfusion injury[J]. J Cell Mol Med, 2021, 25(11): 5060-5069. [14] Liu X B, Xia H, Wang G, et al.Propofol relieves oxidative stress response of cerebral ischemiareperfusion injury through SIRT1 signaling pathway[J]. J Biol Regul Homeost Agents, 2020, 34(3): 435-443. [15] Guan X, Li Z, Zhu S, et al.Galangin attenuated cerebral ischemia-reperfusion injury by inhibition of ferroptosis through activating the SLC7A11/GPX4 axis in gerbils[J]. Life Sic, 2021, 264: 118660. [16] Xuan W, Lu X, Yang Z, et al.Propofol Protects Against Erastin-Induced Ferroptosis in HT-22 Cells[J]. J Mol Neurosic, 2022, 72(9): 1797-1808. [17] Fan GB, Li Y, Xu GS, et al.Propofol Inhibits Ferroptotic Cell Death Through the Nrf2/Gpx4 Signaling Pathway in the Mouse Model of Cerebral Ischemia-Reperfusion Injury[J]. Neurochem Res, 2023, 48(3): 956-966. [18] Liu Z, Li C, Li Y, et al.Propofol Reduces Renal Ischemia Reperfusion-mediated Necroptosis by Up-regulation of SIRT1 in Rats[J]. Inflammation, 2022, 45(5): 2038-2051. [19] Lu Z, Shen J, Chen X, et al.Propofol Upregulates MicroRNA-30b to Inhibit Excessive Autophagy and Apoptosis and Attenuates Ischemia/Reperfusion Injury In Vitro and in Patients[J]. Oxid Med Cell Longe, 2022, 2022: 2109891. [20] Rong Y, Fan J, Ji C, et al.USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1[J]. Cell Death Differ, 2022, 29(6): 1164-1175. [21] Chen HY, Xiao ZZ, Ling X, et al.ELAVL1 is transcriptionally activated by FOXC1 and promotes ferroptosis in myocardial ischemia/reperfusion injury by regulating autophagy[J]. Mol Med, 2021, 27(1): 14. [22] Shimada S, Hirabayashi M, Ishige K, et al.Activation of dopamine D4 receptors is protective against hypoxia/reoxygenation-induced cell death in HT22 cells[J]. J Pharmacol Sci, 2010, 114(2): 217-224. [23] Zhang Y, Zhang Y, Jin XF, et al.The Role of Astragaloside IV against Cerebral Ischemia/Reperfusion Injury: Suppression of Apoptosis via Promotion of P62-LC3-Autophagy[J]. Molecules, 2019, 24(9): 1838. [24] Zhang Y, Yao Z, Xiao Y, et al.Downregulated XBP-1 Rescues Cerebral Ischemia/Reperfusion Injury-Induced Pyroptosis via the NLRP3/Caspase-1/GSDMD Axis[J]. Mediators Inflamm, 2022, 2022: 8007078.
2023, Vol. 20 
