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Acupuncture inhibits astrocytic hyperactivation via the p38 mitogen-activated protein kinase/mitogen- and stress-activated protein kinase 1 signaling pathway in cerebral ischemia-reperfusion injury
Received date: 2025-06-11
Accepted date: 2025-11-10
Online published: 2026-04-04
Supported by
Guangzhou Basic and Applied Basic Research Foundation: Mechanistic Investigation of Ziwu Liuzhu Acupuncture for Insomnia Based on the Heat Shock Protein 90/Stimulator of Interferon Genes-nuclear Factor Kappa B Immune Pathway and Its Regulation of Sleep-Wake Rhythms(2025A03J3400);Guangdong Basic and Applied Basic Research Foundation: Danggui Sini Decoction Promotes Damaged Nerve Repair and Treats Sciatica by Inhibiting Secreted Phosphoprotein 1/Cluster of Differentiation 44-Mediated Macrophage-Schwann Cell Crosstalk(2025A1515011267);Guangzhou Doctoral Start-up Program: Danggui Sini Decoction Regulates Angiopoietin-like 4/Syndecan-4-mediated Neurovascular Coupling to Promote Injured Nerve Repair for the Treatment of Sciatica(2025A04J3397);National Natural Science Foundation of China (Youth Program): Investigation of Danggui Sini Decoction in Improving Neuro-microcirculation and Promoting Nerve Repair for the Treatment of Sciatica Based on Angptl4/Sdc4-mediated Endothelial Cell-Schwann Cell Coupling(82405081);China Postdoctoral Science Foundation Special Funding (Pre-Station): Danggui Sini Decoction Inhibits Peripheral Sensitization and Alleviates Sciatica by Regulating Macrophage-neuron Crosstalk(2023TQ0135);China Postdoctoral Science Foundation General Funding: Danggui Sini Decoction Promotes Damaged Nerve Repair and Treats Sciatica by Modulating Endothelial Cell-schwann Cell Coupling(2024M751136)
OBJECTIVE: To observe the effect of acupuncture on astrocyte activation following cerebral ischemia-reperfusion injury (CIRI) viathe p38 mitogen-activated protein kinase (p38 MAPK)/mitogen- and stress-activated protein kinase 1 (MSK1) signaling pathway.
METHODS: Transcriptome and single-cell sequencing were used to analyse gene expression in middle cerebral artery occlusion (MCAO)-induced rats. Acupuncture was applied at Baihui (GV20) and Dazhui (GV14) for 7 d. The infarct volume was assessed via2,3,5-triphenyltetrazolium chloride staining and T2-weighted imaging. Serum interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha levels were measured viaenzyme-linked immunosorbent assay. The expression of glial fibrillary acidic protein (GFAP), complement component 3 (C3), and S100 calcium-binding protein A10 (S100A10), as well as components of the p38 MAPK/MSK1 pathway, was examined by Western blotting and immunohistochemistry.
RESULTS: CIRI activated p38 MAPK signaling, increased the expression of A1 markers (GFAP and C3), and proinflammatory cytokines, and decreased the expression of the A2 marker S100A10. Acupuncture inhibited p38 phosphorylation, upregulated MSK1, reduced C3 and inflammatory cytokines, increased S100A10 expression, decreased infarct volume, and improved neurological function.
CONCLUSION: Acupuncture protects against ischemic stroke by targeting the p38 MAPK/MSK1 pathway. It inhibits p38 MAPK phosphorylation and activates MSK1, thereby promoting a shift in astrocyte polarization from the pro-inflammatory A1 to the reparative A2 type, as reflected by decreased C3 and increased S100A10 expression. This shift reduces pro-inflammatory cytokines, alleviates cerebral inflammation, and promotes neural repair, ultimately diminishing infarct volume, restoring neurons, and improving behavior. These findings elucidate the mechanism of acupuncture and support its clinical use.
ZHUANG Zifeng , WO Choying , CHEN Hongling , XIE Hailiang , ZHAO Canghuan , ZHANG Di , QING Peng . Acupuncture inhibits astrocytic hyperactivation via the p38 mitogen-activated protein kinase/mitogen- and stress-activated protein kinase 1 signaling pathway in cerebral ischemia-reperfusion injury[J]. Journal of Traditional Chinese Medicine, 2026 , 46(2) : 316 -325 . DOI: 10.19852/j.cnki.jtcm.2026.02.005
| 1. | Luo S, Yang F, Chen YC, et al. Sanhua Tang protects against ischemic stroke by preventing blood-brain barrier injury: a network pharmacology and experiments. J Tradit Chin Med 2024; 44: 794-803. |
| 2. | Collaborators GBDA. The burden and trend of diseases and their risk factors in Australia, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Public Health 2023; 8: e585-e99. |
| 3. | Musuka TD, Wilton SB, Traboulsi M, et al. Diagnosis and management of acute ischemic stroke: speed is critical. CMAJ 2015; 187: 887-93. |
| 4. | Catanese L, Tarsia J, Fisher M. Acute ischemic stroke therapy overview. Circ Res 2017; 120: 541-58. |
| 5. | Jiang JL, Tao YU, Qian YL, Wang M. Understanding the role of microglia in Alzheimer's disease: insights into mechanisms, acupuncture, and potential therapeutic targets. J Tradit Chin Med 2025; 45: 922-36. |
| 6. | Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010; 119: 7-35. |
| 7. | Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p 38 protein kinases. Science 2002; 298: 1911-2. |
| 8. | Ananieva O, Darragh J, Johansen C, et al. The kinases MSK1 and MSK2 act as negative regulators of toll-like receptor signaling. Nat Immunol 2008; 9: 1028-36. |
| 9. | Sun X, Liu H, Sun Z, et al. Acupuncture protects against cerebral ischemia-reperfusion injury via suppressing endoplasmic reticulum stress-mediated autophagy and apoptosis. Mol Med 2020; 26: 105. |
| 10. | Chen YL, Ouyang L, Meng LL, et al. Electroacupuncture ameliorates blood-brain barrier disruption after ischemic stroke through histone acetylation regulation at the matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 2 genes. J Tradit Chin Med 2024; 44: 734-44. |
| 11. | Li N, Guo Y, Gong Y, et al. The anti-inflammatory actions and mechanisms of acupuncture from acupoint to target organs via neuro-immune regulation. J Inflamm Res 2021; 14: 7191-224. |
| 12. | Zhu W, Ye Y, Liu Y, et al. Mechanisms of acupuncture therapy for cerebral ischemia: an evidence-based review of clinical and animal studies on cerebral ischemia. J Neuroimmune Pharmacol 2017; 12: 575-92. |
| 13. | Li X, Zhuang Z, Hao Y, et al. Paeonol relieves chronic neuropathic pain by reducing communication between schwann cells and macrophages in the dorsal root ganglia after injury. Int J Mol Sci 2025; 26: 3964. |
| 14. | Li YX, Liao Y, Sun CH, et al. Single-cell sequencing and network pharmacology analyses indicate that Renshen Guben oral liquid alleviates apoptosis to relieve intervertebral disc degeneration. Tradit Med Res 2025; 10: 64. |
| 15. | Si WM, Chen ZN, Bei J, et al. Stigmasterol alleviates neuropathic pain by reducing Schwann cell-macrophage cascade in DRG by modulating IL-34/CSF1R. Cns Neurosci Ther 2024; 30: e14657. |
| 16. | Longa EZ, Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20: 84-91. |
| 17. | Zhang D, Chen ZN, Zhuang ZF, et al. Danggui Sini decoction normalizes the intestinal microbiota and serum metabolite levels to treat sciatica. Phytomedicine 2024; 132: 155740. |
| 18. | Jing B, Chen ZN, Si WM, et al.(+)-Catechin attenuates CCI-induced neuropathic pain in male rats by promoting the Nrf2 antioxidant pathway to inhibit ROS/TLR4/NF-kappa B-mediated activation of the NLRP3 inflammasome. J Neurosci Res 2024; 102: e25372. |
| 19. | Jing B, Zhao JJ, Chen ZN, et al. (+)-Catechin alleviates CCI-induced neuropathic pain by modulating microglia M1 and M2 polarization via the TLR4/MyD88/NF-kappa B signaling pathway. J Neuroimmune Pharmacol 2025; 20: 33. |
| 20. | Wang Y, Liu XX, Guo Y, et al. Characterization of acupuncture on central amino acid metabolism based on targeted neurotransmitter analysis in mice with inflammatory pain. J Tradit Chin Med 2025; 45: 1019-27. |
| 21. | Hu M, Zhang X, Liu W, et al. Longitudinal changes of defensive and offensive factors in focal cerebral ischemia-reperfusion in rats. Brain Res Bull 2009; 79: 371-5. |
| 22. | Jurcau A, Ardelean IA. Molecular pathophysiological mechanisms of ischemia/reperfusion injuries after recanalization therapy for acute ischemic stroke. J Integr Neurosci 2021; 20: 727-44. |
| 23. | Jurcau A, Simion A. Neuroinflammation in cerebral ischemia and ischemia/reperfusion injuries: from pathophysiology to therapeutic strategies. Int J Mol Sci 2022; 23: 14. |
| 24. | Zheng K, Lin L, Jiang W, et al. Single-cell RNA-seq reveals the transcriptional landscape in ischemic stroke. J Cereb Blood Flow Metab 2022; 42: 56-73. |
| 25. | Ruan Z, Cao G, Qian Y, et al. Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia-reperfusion injury by modulating various cells. J Neuroinflammation 2023; 20: 285. |
| 26. | Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541: 481-7. |
| 27. | Miyamoto N, Magami S, Inaba T, et al. The effects of A1/A2 astrocytes on oligodendrocyte linage cells against white matter injury under prolonged cerebral hypoperfusion. Glia 2020; 68: 1910-24. |
| 28. | Cieri MB, Ramos AJ. Astrocytes, reactive astrogliosis, and glial scar formation in traumatic brain injury. Neural Regen Res 2025; 20: 973-89. |
| 29. | Kim JH, Choi KH, Jang YJ, et al. Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice. PLoS One 2013; 8: e56736. |
| 30. | Lu TL, Luo Y, Sun HY, et al. Electroacupuncture improves behavioral recovery and increases SCF/c-kit expression in a rat model of focal cerebral ischemia/reperfusion. Neurol Sci 2013; 34: 487-95. |
| 31. | Kim YR, Kim HN, Ahn SM, et al. Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One 2014; 9: e90000. |
| 32. | Chavez LM, Huang SS, MacDonald I, et al. Mechanisms of acupuncture therapy in ischemic stroke rehabilitation: a literature review of basic studies. Int J Mol Sci 2017; 18: 2270. |
| 33. | LI ST, Wang SJ, Yin YH, et al. Electroacupuncture alleviates zymosan-induced colorectal hypersensitivity. J Tradit Chin Med 2025; 45: 32-8. |
| 34. | Sun M, Song Y, Hu X, et al. Leptin reduces LPS-induced A1 reactive astrocyte activation and inflammation via inhibiting p38-MAPK signaling pathway. Glia 2025; 73: 25-37. |
| 35. | Zhang D, Jing B, Chen Z, et al. Ferulic acid alleviates sciatica by inhibiting peripheral sensitization through the RhoA/p38MAPK signalling pathway. Phytomedicine 2022; 106: 154420. |
| 36. | Boulton TG, Nye SH, Robbins DJ, et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 1991; 65: 663-75. |
| 37. | Arthur JS. MSK activation and physiological roles. Front Biosci 2008; 13: 5866-79. |
| 38. | Cooper DD, Frenguelli BG. The influence of sensory experience on the glutamatergic synapse. Neuropharmacology 2021; 193: 108620. |
| 39. | Reyskens KM, Arthur JS. Emerging roles of the mitogen and stress activated kinases MSK1 and MSK2. Front Cell Dev Biol 2016; 4: 56. |
| 40. | Lan X, Zhang X, Zhou GP, et al. Electroacupuncture reduces apoptotic index and inhibits p38 mitogen-activated protein kinase signaling pathway in the hippocampus of rats with cerebral ischemia/reperfusion injury. Neural Regen Res 2017; 12: 409-16. |
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