Skip to main content

Advertisement

SpringerLink
Log in

Transcutaneous Electrical Acupoint Stimulation Pretreatment Alleviates Cerebral Ischemia–Reperfusion Injury in Rats by Modulating Microglia Polarization and Neuroinflammation Through Nrf2/HO-1 Signaling Pathway

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Cerebral ischemia–reperfusion injury (CIRI) may lead to severe disability even death, but the strategies for prevention and treatment are still limited. Transcutaneous electrical acupoint stimulation (TEAS) has been reported to have a significant neuroprotection against CIRI, but the underlying mechanisms remain obscure. In this study, we established a focal cerebral ischemia–reperfusion model in male Sprague-Dawley rats. TEAS pretreatment was applied to Baihui (GV20), Sanyinjiao (SP6) and Zusanli (ST36) acupoints for 5 consecutive days before CIRI. After 24 h reperfusion, the brain damage was assessed using Zea-Longa score, brain water content (BWC) and infarct volume. Meanwhile, the number of activated microglia and the TNF-α were detected by immunofluorescence and ELISA respectively. Moreover, Western Blot and RT-qPCR were conducted to detect the proteins and mRNA expressions of Nrf2, HO-1, iNOS and Arg-1. We found that TEAS pretreatment significantly reduced Longa score, BWC, infarct volume and the number of activated microglia. Besides, TEAS pretreatment increased Nrf2 and HO-1 levels, while lowered the expression of TNF-α. Subsequently, we also discovered that the microglia M1 phenotype maker iNOS decreased and the M2 maker Arg-1 increased after TEAS pretreatment. However, these effects of TEAS pretreatment were markedly eliminated by brusatol. These findings clearly suggested that TEAS pretreatment exerted neuroprotection against CIRI, which might be related to modulating microglia polarization and neuroinflammation via Nrf2/HO-1 pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Zheng L, Tang X, Lu M, Sun S, Xie S, Cai J, Zan J (2020) MicroRNA-421-3p prevents inflammatory response in cerebral ischemia/reperfusion injury through targeting m6A reader YTHDF1 to inhibit p65 mRNA translation. Int Immunopharmacol 88:106937. https://doi.org/10.1016/j.intimp.2020.106937

    Article  CAS  PubMed  Google Scholar 

  2. Huang YG, Tao W, Yang SB, Wang JF, Mei ZG, Feng ZT (2019) Autophagy: novel insights into therapeutic target of electroacupuncture against cerebral ischemia/ reperfusion injury. Neural Regen Res 14:954–961. https://doi.org/10.4103/1673-5374.250569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jurcau A, Simion A (2021) Neuroinflammation in cerebral ischemia and ischemia/reperfusion injuries: from pathophysiology to therapeutic strategies. Int J Mol Sci 23:14. https://doi.org/10.3390/ijms23010014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhu J, Li J, Yang L, Liu S (2021) Acupuncture, from the ancient to the current. Anat Rec 304:2365–2371. https://doi.org/10.1002/ar.24625

    Article  Google Scholar 

  5. Wang D, Shi H, Yang Z, Liu W, Qi L, Dong C, Si G, Guo Q (2022) Efficacy and safety of transcutaneous electrical acupoint stimulation for postoperative pain: a meta-analysis of randomized controlled trials. Pain Res Manag. https://doi.org/10.1155/2022/7570533

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yang Y, Yang X, Dong Y, Chen N, Xiao X, Liu H, Li Z, Chen Y (2016) Transcutaneous electrical acupoint stimulation alleviates adverse cardiac remodeling induced by overload training in rats. J Appl Physiol 120:1269–1276. https://doi.org/10.1152/japplphysiol.00077.2016

    Article  CAS  PubMed  Google Scholar 

  7. Ni X, Xie Y, Wang Q, Zhong H, Chen M, Wang F, Xiong L (2012) Cardioprotective effect of transcutaneous electric acupoint stimulation in the pediatric cardiac patients: a randomized controlled clinical trial. Paediatr Anaesth 22:805–811. https://doi.org/10.1111/j.1460-9592.2012.03822.x

    Article  PubMed  Google Scholar 

  8. Xiong W, Zhao CM, An LX, Xie SN, Jia CR (2020) Efficacy of acupuncture combined with local anesthesia in ischemic stroke patients with carotid artery stenting: a prospective randomized trial. Chin J Integr Med 26:609–616. https://doi.org/10.1007/s11655-019-3174-8

    Article  CAS  PubMed  Google Scholar 

  9. Harry GJ (2021) Microglia in neurodegenerative events-an initiator or a significant other? Int J Mol Sci 22:5818. https://doi.org/10.3390/ijms22115818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Farina M, Vieira LE, Buttari B, Profumo E, Saso L (2021) The Nrf2 pathway in ischemic stroke: a review. Molecules 26:5001. https://doi.org/10.3390/molecules26165001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gao J, Chen N, Li N, Xu F, Wang W, Lei Y, Shi J, Gong Q (2020) Neuroprotective effects of trilobatin, a novel naturally occurring Sirt3 agonist from Lithocarpus polystachyus Rehd., mitigate cerebral ischemia/reperfusion injury: involvement of TLR4/NF-κB and Nrf2/Keap-1 signaling. Antioxid Redox Signal 33:117–143. https://doi.org/10.1089/ars.2019.7825

    Article  CAS  PubMed  Google Scholar 

  12. Shen Y, Liu X, Shi J, Wu X (2019) Involvement of Nrf2 in myocardial ischemia and reperfusion injury. Int J Biol Macromol 125:496–502. https://doi.org/10.1016/j.ijbiomac.2018.11.190

    Article  CAS  PubMed  Google Scholar 

  13. Landis RC, Quimby KR, Greenidge AR (2018) M1/M2 macrophages in diabetic nephropathy: Nrf2/HO-1 as therapeutic targets. Curr Pharm Des 24:2241–2249. https://doi.org/10.2174/1381612824666180716163845

    Article  CAS  PubMed  Google Scholar 

  14. Michaličková D, Hrnčíř T, Canová NK, Slanař O (2020) Targeting Keap1/Nrf2/ARE signaling pathway in multiple sclerosis. Eur J Pharmacol 873:172973. https://doi.org/10.1016/j.ejphar.2020.172973

    Article  CAS  PubMed  Google Scholar 

  15. Subedi L, Lee JH, Yumnam S, Ji E, Kim SY (2019) Anti-Inflammatory effect of sulforaphane on LPS-activated microglia potentially through JNK/AP-1/NF-κB Inhibition and Nrf2/HO-1 activation. Cells 8:194. https://doi.org/10.3390/cells8020194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bi F, Zhang Y, Liu W, Xie K (2021) Sinomenine activation of Nrf2 signaling prevents inflammation and cerebral injury in a mouse model of ischemic stroke. Exp Ther Med 21:647. https://doi.org/10.3892/etm.2021.10079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91. https://doi.org/10.1161/01.str.20.1.84

    Article  CAS  PubMed  Google Scholar 

  18. Bai YY, Yan D, Zhou HY, Li WX, Lou YY, Zhou XR, Qian LB, Xiao C (2020) Betulinic acid attenuates lipopolysaccharide-induced vascular hyporeactivity in the rat aorta by modulating Nrf2 antioxidative function. Inflammopharmacology 28:165–174. https://doi.org/10.1007/s10787-019-00622-4

    Article  CAS  PubMed  Google Scholar 

  19. Xue Y, Nie D, Wang LJ, Qiu HC, Ma L, Dong MX, Tu WJ, Zhao J (2021) Microglial polarization: novel therapeutic strategy against ischemic stroke. Aging Dis 12:466–479. https://doi.org/10.14336/AD.2020.0701

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhang T, Ou L, Chen Z, Li J, Shang Y, Hu G (2021) Transcutaneous electrical acupoint stimulation for the prevention of postoperative cognitive dysfunction: a systematic review and meta-analysis. Front Med 8:756366. https://doi.org/10.3389/fmed.2021.756366

    Article  Google Scholar 

  21. Long M, Wang Z, Shao L, Bi J, Chen Z, Yin N (2022) Electroacupuncture pretreatment attenuates cerebral ischemia-reperfusion injury in rats through transient receptor potential vanilloid 1-mediated anti-apoptosis via inhibiting NF-κB signaling pathway. Neuroscience 482:100–115. https://doi.org/10.1016/j.neuroscience.2021.12.017

    Article  CAS  PubMed  Google Scholar 

  22. Wang X, Ding R, Song Y, Wang J, Zhang C, Han S, Han J, Zhang R (2020) Transcutaneous electrical acupoint stimulation in early life changes synaptic plasticity and improves symptoms in a valproic acid-induced rat model of autism. Neural Plast 2020:8832694. https://doi.org/10.1155/2020/8832694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gao F, Zhang Q, Li Y, Tai Y, Xin X, Wang X, Wang Q (2018) Transcutaneous electrical acupoint stimulation for prevention of postoperative delirium in geriatric patients with silent lacunar infarction: a preliminary study. Clin Interv Aging 13:2127–2134. https://doi.org/10.2147/cia.S183698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mei ZG, Huang YG, Feng ZT, Luo YN, Yang SB, Du LP, Jiang K, Liu XL, Fu XY, Deng YH, Zhou HJ (2020) Electroacupuncture ameliorates cerebral ischemia/reperfusion injury by suppressing autophagy via the SIRT1-FOXO1 signaling pathway. Aging 12:13187–13205. https://doi.org/10.18632/aging.103420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Woodburn SC, Bollinger JL, Wohleb ES (2021) The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflamm 18:258. https://doi.org/10.1186/s12974-021-02309-6

    Article  Google Scholar 

  26. Lin X, Zhan J, Jiang J, Ren Y (2021) Upregulation of neuronal cylindromatosis expression is essential for electroacupuncture-mediated alleviation of neuroinflammatory injury by regulating microglial polarization in rats subjected to focal cerebral ischemia/reperfusion. J Inflamm Res 14:2061–2078. https://doi.org/10.2147/JIR.S307841

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang N, Nie H, Zhang Y, Han H, Wang S, Liu W, Tian K (2022) Dexmedetomidine exerts cerebral protective effects against cerebral ischemic injury by promoting the polarization of M2 microglia via the Nrf2/HO-1/NLRP3 pathway. Inflamm Res 71:93–106. https://doi.org/10.1007/s00011-021-01515-5

    Article  CAS  PubMed  Google Scholar 

  28. Li QQ, Ding DH, Wang XY, Sun YY, Wu J (2021) Lipoxin A4 regulates microglial M1/M2 polarization after cerebral ischemia-reperfusion injury via the Notch signaling pathway. Exp Neurol 339:113645. https://doi.org/10.1016/j.expneurol.2021.113645

    Article  CAS  PubMed  Google Scholar 

  29. Mansouri A, Reiner Ž, Ruscica M, Tedeschi-Reiner E, Radbakhsh S, Bagheri Ekta M, Sahebkar A (2022) Antioxidant effects of statins by modulating Nrf2 and Nrf2/HO-1 signaling in different diseases. J Clin Med 11:1313. https://doi.org/10.3390/jcm11051313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang L, Guo Y, Ye J, Pan Z, Hu P, Zhong X, Qiu F, Zhang D, Huang Z (2021) Protective effect of piceatannol against cerebral ischaemia-reperfusion injury via regulating Nrf2/HO-1 pathway in vivo and vitro. Neurochem Res 46:1869–1880. https://doi.org/10.1007/s11064-021-03328-8

    Article  CAS  PubMed  Google Scholar 

  31. He D, Fu S, Zhou A, Su Y, Gao X, Zhang Y, Huang B, Du J, Liu D (2021) Camptothecin regulates microglia polarization and exerts neuroprotective effects via activating AKT/Nrf2/HO-1 and inhibiting NF-κB pathways in vivo and in vitro. Front Immunol 12:619761. https://doi.org/10.3389/fimmu.2021.619761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ruan ZF, Xie M, Gui SJ, Lan F, Wan J, Li Y (2020) MiR-370 accelerated cerebral ischemia reperfusion injury via targeting SIRT6 and regulating Nrf2/ARE signal pathway. Kaohsiung J Med Sci 36:741–749. https://doi.org/10.1002/kjm2.12219

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Prof. Han-Ying Xing in the Clinical Medicine Research Center of Hebei General Hospital for her technical support in Western Blot

Funding

This study was supported by Hebei Provincial Government Funded Excellent Talents Training Project of Clinical Medicine in 2022 (JCS [2022] 016).

Author information

Author notes

  1. Jianli Li and Mengdi Hao have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Anesthesiology, Hebei General Hospital, Shijiazhuang, Hebei, China

    Jianli Li, Mengdi Hao, Meinv Liu, Jing Wang, Dongyan Gao, Shuang Han & Dongdong Yu

Authors
  1. Jianli Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mengdi Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meinv Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongyan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuang Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dongdong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JL and MH contributed to design of the study and drafted the original manuscript; ML and MH conducted data collection and researched; JW and DG purchased animals and material instruments and participated in the establishment of animal model. SH and DY contributed to data analysis. JL and ML revised the final version of the manuscript. All authors approved the submitted version.

Corresponding author

Correspondence to Jianli Li.

Ethics declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

All experiments adhered to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals, and the study was approved by Hebei General Hospital Animal Ethics Committee (Date: 2021–12-14 / Number: 2021–270).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 91 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Hao, M., Liu, M. et al. Transcutaneous Electrical Acupoint Stimulation Pretreatment Alleviates Cerebral Ischemia–Reperfusion Injury in Rats by Modulating Microglia Polarization and Neuroinflammation Through Nrf2/HO-1 Signaling Pathway. Neurochem Res 48, 862–873 (2023). https://doi.org/10.1007/s11064-022-03797-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-022-03797-5

Keywords

Search

Navigation