Electroacupuncture of the Auricular Vagus Nerve Alleviates Glial Scar Formation in Astrocytes and Promotes Neuroprotection after Cerebral Ischemia–Reperfusion in Rats via the NF-κB Signaling Pathway
DOI:
https://doi.org/10.62836/amr.v5i2.0011Keywords:
auricular vagus nerve stimulation, electroacupuncture, ischemic stroke, glial scar, astrocyte, NF-κB, neuroinflammationAbstract
Background: Ischemic stroke is a leading cause of death and long-term disability worldwide. Auricular vagus nerve stimulation (aVNS), delivered as electroacupuncture to the auricular concha, improves neurological outcome after cerebral ischemia–reperfusion (I/R), but the underlying molecular mechanism, particularly its effect on astrocytic reactive gliosis and glial scar formation, remains incompletely defined. Objectives: This study tested the hypothesis that aVNS alleviates astrocytic glial scar formation and promotes neuroprotection after I/R, and that the NF-κB signaling pathway is a key mediator of this effect. Methods: Male Sprague–Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and randomly assigned to Sham, Model, PBS (vehicle), and aVNS groups. A separate cohort of IKKβ-knockout (IKKβ-KO) rats was used to dissect the role of NF-κB signaling. Neurological function was assessed by the modified neurological severity score (mNSS) and the adhesive-removal somatosensory test (ARST) at 7 and 14 days. Glial scar markers (GFAP, neurocan, phosphacan) and NF-κB pathway components (p-p65, p-IκBα) were quantified by qRT-PCR, Western blot, and immunofluorescence. Results: aVNS significantly improved mNSS and ARST and reduced cortical GFAP, neurocan, and phosphacan mRNA and protein expression compared with the Model group (all p < 0.05). aVNS also reduced phosphorylation of p65 and IκBα, indicating inhibition of NF-κB signaling. In IKKβ-KO rats, the aVNS-mediated suppression of glial scar markers and neuroprotection was largely abolished, confirming the involvement of NF-κB signaling. Conclusions: aVNS alleviates post-ischemic astrocytic glial scar formation and promotes neuroprotection through inhibition of the NF-κB signaling pathway. These findings identify NF-κB as a molecular target underlying the therapeutic effect of aVNS and support its clinical translation in post-stroke rehabilitation.
References
Jayaraj RL, Azimullah S, Beiram R, et al. Neuroinflammation: Friend and Foe for Ischemic Stroke. Journal of neuroinflammation 2019; 16(1): 142.
Wang YJ, Li ZX, Gu HQ, et al. China Stroke Statistics 2019: A Report from the National Center for Healthcare Quality Management in Neurological Diseases. Stroke and Vascular Neurology 2020; 5(3): 211–239.
Tang Y, Wang J, Lin X, et al. Neural Stem Cell Protects Aged Rat Brain from Ischemia-Reperfusion Injury through Neurogenesis and Angiogenesis. Journal of Cerebral Blood Flow & Metabolism 2014; 34(7): 1138–1147.
Keute M, Gharabaghi A. Brain Plasticity and Vagus Nerve Stimulation. Autonomic Neuroscience 2021; 236: 102876.
Yang J, Jia N, Ou Z, et al. The Alleviation of Variable-Frequency aVNS on Neuroinflammatory Injury in Ischemia-Reperfusion Rats Is Related to the Inhibition of TLR4 Expression. Minerva Medica 2024; 115(2): 214–215
Yang J. The Effect of Variable-Frequency aVNS on Rats with Cerebral Ischemia-Reperfusion Injury and Its Regulation of the Downstream Signaling Pathways of α7nAChR and TLR4 Activation to Induce Microglial Polarization; Sichuan University: Chengdu, China, 2022.
Ay I, Napadow V, Ay H. Electrical Stimulation of the Vagus Nerve Dermatome in the External Ear Is Protective in Rat Cerebral Ischemia. Brain Stimulation 2015; 8(1): 7–12.
Jiang Y, Li L, Liu B, et al. Vagus Nerve Stimulation Attenuates Cerebral Ischemia and Reperfusion Injury via Endogenous Cholinergic Pathway in Rat. PLoS ONE 2014; 9(7): e102342.
Capone F, Miccinilli S, Pellegrino G, et al. Transcutaneous Vagus Nerve Stimulation Combined with Robotic Rehabilitation Improves Upper Limb Function after Stroke. Neural Plasticity 2017; 2017: 7876507.
Zhao K, Yang J, Huang J, et al. Effect of Vagus Nerve Stimulation Paired with Rehabilitation for Upper Limb Function Improvement after Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. International Journal of Rehabilitation Research 2022; 45(2): 99–108.
Yang JE, Jia N. Advances of Research on Auricular Vagus Nerve Stimulation for Treatment of Nervous System Diseases. Journal of Biosciences and Medicines 2023; 11: 1–14.
Zhang L, Liu Y, Wang S, et al. Vagus Nerve Stimulation Mediates Microglia M1/2 Polarization via Inhibition of TLR4 Pathway after Ischemic Stroke. Biochemical and Biophysical Research Communications 2021; 577: 71–79.
Qin C, Zhou LQ, Ma XT, et al. Dual Functions of Microglia in Ischemic Stroke. Neuroscience Bulletin 2019; 35(5): 921–933.
Franco R, Fernandez-Suarez D. Alternatively Activated Microglia and Macrophages in the Central Nervous System. Progress in Neurobiology 2015; 131: 65–86.
Ma YY, Wang JX, Wang YT, et al. The biphasic function of microglia in ischemic stroke. Progress in Neurobiology 2017; 157: 247–272.
Kamermans A, Planting KE, Jalink K, et al. Reactive Astrocytes in Multiple Sclerosis Impair Neuronal Outgrowth through TRPM7-Mediated Chondroitin Sulfate Proteoglycan Production. Glia 2019; 67(1): 68–77.
Adams KL, Gallo V. The Diversity and Disparity of the Glial Scar. Nature neuroscience 2018; 21(1): 9–15.
Gaire BP, Choi JW. Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses. International Journal of Molecular Sciences 2021; 22(15): 7864.
Zhong K, Wang RX, Qian XD, et al. Neuroprotective Effects of Saffron on the Late Cerebral Ischemia Injury through Inhibiting Astrogliosis and Glial Scar Formation in Rats. Biomedicine & Pharmacotherapy 2020; 126: 110041.
Sun Z, Shi K, Yang S, et al. Effect of Exosomal miRNA on Cancer Biology and Clinical Applications. Molecular Cancer 2018;17(1):147.
Yang J, Huang Y, Li Q, et al. Activation of NF-κB Signaling in Cerebral Ischemia-Reperfusion Injury. Journal of Neuroinflammation 2020; 17(1): 96.
Zhao Y, Gan Y, Xu G, et al. Exosomes from MSCs Overexpressing microRNA-223-3p Attenuate Cerebral Ischemia through Inhibiting Microglial M1 Polarization Mediated Inflammation. Life Science 2020; 260: 118367.
Png KJ, Halberg N, Yoshida M, et al. A microRNA Regulon That Mediates Endothelial Recruitment and Metastasis by Cancer Cells. Nature 2011; 481(7380): 190–194.
Cheng CY, Chiang SY, Kao ST, et al. Alpinia Oxyphylla Miq Extract Reduces Cerebral Infarction by Downregulating JNK-Mediated Inflammatory Signaling in the Acute Phase of Transient Focal Cerebral Ischemia in Rats. Chinese Medicine 2021; 16(1): 82.
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Copyright (c) 2026 Jiaen Yang, Chuanlin Lu, Lihui Yu, Guangjin Zhou, Ning Jia
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