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Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Electroacupuncture Inhibits Ferroptosis Induced by Cerebral Ischemiareperfusion

Author(s): Gui-Ling Wang, Shu-Ying Xu, He-Qun Lv, Chao Zhang and Yong-Jun Peng*

Volume 20, Issue 3, 2023

Published on: 24 August, 2023

Page: [346 - 353] Pages: 8

DOI: 10.2174/1567202620666230623153728

Price: $65

Abstract

Background: Electroacupuncture (EA) treatment has been recommended by World Health Organization (WHO) for years on cerebral ischemia treatment, but the specific mechanism is still elusive. Studies have shown that EA can relieve brain damage after ischemic stroke by inhibiting programmed cell death (PCD), such as apoptosis, necroptosis, and autophagy. Ferroptosis, a unique form of cell death, has been highlighted recently and found to occur in I/R injury. We, therefore, investigated whether EA plays an essential role in relieving cerebral I/R injury via ferroptosis.

Methods: The modified MCAO/R rats model was established and then divided into four groups with or without EA treatment. Neurological deficit score and TTC staining were used to evaluate the neurological deficit and infarct volume of each group. Transmission electron microscope (TEM) and immunofluorescence staining were applied for mitochondrial ultrastructure and ROS accumulation observation, respectively. The proteins and mRNA expression of ACSL4, TFR1, and GPX4 were assessed by western blot and qPCR to detect the progress of ferroptosis.

Results: EA treatment improved neurological deficits and reduced infarct volume. Moreover, EA significantly relieved the mitochondrial morphological changes and inhibited ROS Production in MCAO rats. In terms of its mechanism, EA obviously decreased the ACSL4 and TFR1 expressions and promoted GPX4 levels in MCAO/R model rats.

Conclusion: These findings indicate that EA might play an essential role in relieving cerebral I/R injury via ferroptosis.

Keywords: Electroacupuncture, ferroptosis, cerebral ischemia/reperfusion, mitochondria, programmed cell death, MCAO rats.

[1]
Johnson CO, Nguyen M, Roth GA, et al. Global, regional, and national burden of stroke, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(5): 439-58.
[http://dx.doi.org/10.1016/S1474-4422(19)30034-1] [PMID: 30871944]
[2]
Feske SK. Ischemic Stroke. Am J Med 2021; 134(12): 1457-64.
[http://dx.doi.org/10.1016/j.amjmed.2021.07.027] [PMID: 34454905]
[3]
Jurcau A, Simion A. Neuroinflammation in cerebral ischemia and ischemia/reperfusion injuries: From pathophysiology to therapeutic strategies. Int J Mol Sci 2021; 23(1): 14.
[http://dx.doi.org/10.3390/ijms23010014] [PMID: 35008440]
[4]
Wang H, Chen S, Zhang Y, Xu H, Sun H. Electroacupuncture ameliorates neuronal injury by Pink1/Parkin-mediated mitophagy clearance in cerebral ischemia-reperfusion. Nitric Oxide 2019; 91: 23-34.
[http://dx.doi.org/10.1016/j.niox.2019.07.004] [PMID: 31323277]
[5]
Shen M, Jin X, Li P, et al. Electroacupuncture alleviates cerebral ischemia and reperfusion injury via modulation of the ERK1/2 signaling pathway. Neural Regen Res 2016; 11(7): 1090-8.
[http://dx.doi.org/10.4103/1673-5374.187041] [PMID: 27630691]
[6]
Long M, Wang Z, Zheng D, et al. Electroacupuncture pretreatment elicits neuroprotection against cerebral ischemia-reperfusion injury in rats associated with transient receptor potential vanilloid 1-mediated anti-oxidant stress and anti-inflammation. Inflammation 2019; 42(5): 1777-87.
[http://dx.doi.org/10.1007/s10753-019-01040-y] [PMID: 31190106]
[7]
Xing Y, Yang SD, Wang MM, Dong F, Feng YS, Zhang F. Electroacupuncture alleviated neuronal apoptosis following ischemic stroke in rats via midkine and ERK/JNK/p38 signaling pathway. J Mol Neurosci 2018; 66(1): 26-36.
[http://dx.doi.org/10.1007/s12031-018-1142-y] [PMID: 30062439]
[8]
Liu L, Zhang Q, Xie HY, et al. Differences in post-ischemic motor recovery and angiogenesis of MCAO rats following electroacupuncture at different acupoints. Curr Neurovasc Res 2020; 17(1): 71-8.
[http://dx.doi.org/10.2174/1567202617666191223151553] [PMID: 31870267]
[9]
Choi KH, Yeon SH, Cho SJ, et al. Biological safety of Electroacupuncture with STS316 needles. BMC Complement Altern Med 2019; 19(1): 285.
[http://dx.doi.org/10.1186/s12906-019-2674-6] [PMID: 31660945]
[10]
Chen C, Yu Q, Xu K, et al. Electroacupuncture pretreatment prevents ischemic stroke and inhibits Wnt signaling-mediated autophagy through the regulation of GSK-3β phosphorylation. Brain Res Bull 2020; 158: 90-8.
[http://dx.doi.org/10.1016/j.brainresbull.2020.03.002] [PMID: 32142833]
[11]
Cao S, Yang Y, Yu Q, Shu S, Zhou S. Electroacupuncture alleviates ischaemic brain injury by regulating the miRNA-34/Wnt/autophagy axis. Brain Res Bull 2021; 170: 155-61.
[http://dx.doi.org/10.1016/j.brainresbull.2021.02.002] [PMID: 33556563]
[12]
Xu SY, Lv HQ, Li WQ, Hong H, Peng YJ, Zhu BM. Electroacupuncture alleviates cerebral ischemia/reperfusion injury in rats by histone H4 lysine 16 acetylation-mediated autophagy. Front Psychiatry 2020; 11: 576539.
[http://dx.doi.org/10.3389/fpsyt.2020.576539] [PMID: 33391046]
[13]
Franke M, Bieber M, Kraft P, Weber ANR, Stoll G, Schuhmann MK. The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain Behav Immun 2021; 92: 221-31.
[http://dx.doi.org/10.1016/j.bbi.2020.12.009] [PMID: 33307174]
[14]
Przykaza Ł. Understanding the connection between common stroke comorbidities, their associated inflammation, and the course of the cerebral ischemia/reperfusion cascade. Front Immunol 2021; 12: 782569.
[http://dx.doi.org/10.3389/fimmu.2021.782569] [PMID: 34868060]
[15]
Orellana-Urzúa S, Rojas I, Líbano L, Rodrigo R. Pathophysiology of ischemic stroke: Role of oxidative stress. Curr Pharm Des 2020; 26(34): 4246-60.
[http://dx.doi.org/10.2174/1381612826666200708133912] [PMID: 32640953]
[16]
Crack P, Wong C. Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia-reperfusion injury. Curr Med Chem 2008; 15(1): 1-14.
[http://dx.doi.org/10.2174/092986708783330665] [PMID: 18220759]
[17]
Wu M, Gu X, Ma Z. Mitochondrial quality control in cerebral ischemia–reperfusion injury. Mol Neurobiol 2021; 58(10): 5253-71.
[http://dx.doi.org/10.1007/s12035-021-02494-8] [PMID: 34275087]
[18]
Gong L, Tang Y, An R, Lin M, Chen L, Du J. RTN1-C mediates cerebral ischemia/reperfusion injury via ER stress and mitochondria-associated apoptosis pathways. Cell Death Dis 2017; 8(10): e3080.
[http://dx.doi.org/10.1038/cddis.2017.465] [PMID: 28981095]
[19]
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5): 1060-72.
[http://dx.doi.org/10.1016/j.cell.2012.03.042] [PMID: 22632970]
[20]
Xu Y, Li K, Zhao Y, Zhou L, Liu Y, Zhao J. Role of Ferroptosis in Stroke. Cell Mol Neurobiol 2023; 43(1): 205-22.
[http://dx.doi.org/10.1007/s10571-022-01196-6] [PMID: 35102454]
[21]
Guo J, Tuo Q, Lei P. Iron, ferroptosis, and ischemic stroke. J Neurochem 2023; 165(4): 487-520.
[http://dx.doi.org/10.1111/jnc.15807] [PMID: 36908209]
[22]
Ratan RR. The chemical biology of ferroptosis in the central nervous system. Cell Chem Biol 2020; 27(5): 479-98.
[http://dx.doi.org/10.1016/j.chembiol.2020.03.007] [PMID: 32243811]
[23]
Li X, Ma N, Xu J, et al. Targeting ferroptosis: Pathological mechanism and treatment of ischemia-reperfusion injury. Oxid Med Cell Longev 2021; 2021: 1-14.
[http://dx.doi.org/10.1155/2021/1587922] [PMID: 34745412]
[24]
Peng Y-J, Xu S-Y, Zeng C-L, Ni S-M. The angiogenesis effects of electro-acupuncture treatment via exosomal miR-210 in cerebral ischemia-reperfusion rats. Curr Neurovasc Res 2022; 19(1): 61-72.
[http://dx.doi.org/10.2174/1567202619666220321115412] [PMID: 35319370]
[25]
Chi L, Du K, Liu D, Bo Y, Li W. Electroacupuncture brain protection during ischemic stroke: A role for the parasympathetic nervous system. J Cereb Blood Flow Metab 2018; 38(3): 479-91.
[http://dx.doi.org/10.1177/0271678X17697988] [PMID: 28281385]
[26]
Zhang W, Han L, Wen Y, Su L, Li Y, Luo X. Electroacupuncture reverses endothelial cell death and promotes angiogenesis through the VEGF/Notch signaling pathway after focal cerebral ischemia‐reperfusion injury. Brain Behav 2023; 13(3): e2912.
[http://dx.doi.org/10.1002/brb3.2912] [PMID: 36786352]
[27]
Li J, Cao F, Yin H, et al. Ferroptosis: Past, present and future. Cell Death Dis 2020; 11(2): 88.
[http://dx.doi.org/10.1038/s41419-020-2298-2] [PMID: 32015325]
[28]
Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022; 185(14): 2401-21.
[http://dx.doi.org/10.1016/j.cell.2022.06.003] [PMID: 35803244]
[29]
Jung YS, Lee SW, Park JH, Seo HB, Choi BT, Shin HK. Electroacupuncture preconditioning reduces ROS generation with NOX4 down-regulation and ameliorates blood-brain barrier disruption after ischemic stroke. J Biomed Sci 2016; 23(1): 32.
[http://dx.doi.org/10.1186/s12929-016-0249-0] [PMID: 26952102]
[30]
Li G, Ye C, Zhu Y, et al. Oxidative Injury in Ischemic Stroke: A Focus on NADPH Oxidase 4. Oxid Med Cell Longev 2022; 2022: 1-12.
[http://dx.doi.org/10.1155/2022/1148874] [PMID: 35154560]
[31]
Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017; 13(1): 81-90.
[http://dx.doi.org/10.1038/nchembio.2238] [PMID: 27842066]
[32]
Küch EM, Vellaramkalayil R, Zhang I, et al. Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1841(2): 227-39.
[http://dx.doi.org/10.1016/j.bbalip.2013.10.018] [PMID: 24201376]
[33]
Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 2019; 26(11): 2284-99.
[http://dx.doi.org/10.1038/s41418-019-0299-4] [PMID: 30737476]
[34]
Cui Y, Zhang Y, Zhao X, et al. ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain Behav Immun 2021; 93: 312-21.
[http://dx.doi.org/10.1016/j.bbi.2021.01.003] [PMID: 33444733]
[35]
Feng H, Schorpp K, Jin J, et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep 2020; 30(10): 3411-3423.e7.
[http://dx.doi.org/10.1016/j.celrep.2020.02.049] [PMID: 32160546]
[36]
Ding H, Yan CZ, Shi H, et al. Hepcidin is involved in iron regulation in the ischemic brain. PLoS One 2011; 6(9): e25324.
[http://dx.doi.org/10.1371/journal.pone.0025324] [PMID: 21957487]
[37]
Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15(3): 234-45.
[http://dx.doi.org/10.1016/j.chembiol.2008.02.010] [PMID: 18355723]
[38]
Okuno K, Naito Y, Yasumura S, et al. Haploinsufficiency of transferrin receptor 1 impairs angiogenesis with reduced mitochondrial complex I in mice with limb ischemia. Sci Rep 2019; 9(1): 13658.
[http://dx.doi.org/10.1038/s41598-019-49983-4] [PMID: 31541184]
[39]
Becker NP, Martitz J, Renko K, et al. Hypoxia reduces and redirects selenoprotein biosynthesis. Metallomics 2014; 6(5): 1079-86.
[http://dx.doi.org/10.1039/C4MT00004H] [PMID: 24700164]
[40]
Gaschler MM, Andia AA, Liu H, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 2018; 14(5): 507-15.
[http://dx.doi.org/10.1038/s41589-018-0031-6] [PMID: 29610484]

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