Open Access
Synergistic Strategies for Ischemic Stroke Revascularization: Unraveling the Role of the Tryptophan-Indole-NETs Axis in Acupuncture and rt-PA Thrombolysis
4
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
4
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
Abstract
Ischemic stroke remains a leading cause of disability and mortality worldwide, with timely revascularization being critical to successful outcomes. While recombinant tissue plasminogen activator (rt-PA) remains the gold standard for thrombolytic therapy, its efficacy is often limited by delayed administration, reperfusion injury, and systemic side effects. Recent research has highlighted the potential of integrative approaches such as acupuncture to enhance the effectiveness and safety of rt-PA therapy. This study investigates the synergistic effects of acupuncture and rt-PA thrombolysis in ischemic stroke treatment, focusing on the regulatory role of the tryptophan-indole-neutrophil extracellular traps (NETs) axis in promoting neurovascular recovery. Using a controlled experimental model, we observed that acupuncture modulates gut microbiota-derived indole metabolites from tryptophan, which in turn downregulate NETs formation—a key mediator of inflammation and thrombosis. The combined treatment not only improved cerebral blood flow and infarct resolution but also reduced neuronal apoptosis and inflammatory markers, suggesting a neuroprotective mechanism. These findings suggest that the tryptophan-indole-NETs axis serves as a critical biological bridge through which acupuncture potentiates rt-PA’s thrombolytic and neurovascular effects. This study offers novel insights into how metabolic and immunological pathways intersect with traditional therapies to improve clinical outcomes in ischemic stroke management and opens new avenues for integrated, precision-based interventions.
How to Cite
Dr. Yuxin Zhang, & Prof. Mei-Lin Huang. (2025). Synergistic Strategies for Ischemic Stroke Revascularization: Unraveling the Role of the Tryptophan-Indole-NETs Axis in Acupuncture and rt-PA Thrombolysis. Frontiers in Business Innovations and Management, 2(04), 33–38. https://doi.org/10.64917/fbim-006
References
Ahmad FB, Anderson RN. The leading causes of death in the US for 2020. JAMA. (2021) 325:1829–30. doi: 10.1001/jama.2021.5469
Mendelson SJ, Prabhakaran S. Diagnosis and Management of Transient Ischemic Attack and Acute Ischemic Stroke: a review. JAMA. (2021) 325:1088–98. doi: 10.1001/jama.2020.26867
Hutten EM, van de Ven AAJM, Mencke R, Pleijhuis RG. Angioedema after use of recombinant tissue-type plasminogen activators in stroke. Stroke. (2024) 55:2193–7. doi: 10.1161/STROKEAHA.124.047060
Hu X, de Silva TM, Chen J, Faraci FM. Cerebral vascular disease and neurovascular injury in ischemic stroke. Circ Res. (2017) 120:449–71. doi: 10.1161/CIRCRESAHA.116.308427
de la Riva P, Marta-Enguita J, Rodríguez-Antigüedad J, Bergareche A, de Munain AL. Understanding endothelial dysfunction and its role in ischemic stroke after the outbreak of recanalization therapies. Int J Mol Sci. (2024) 25:11631. doi: 10.3390/ijms252111631
Shi K, Zou M, Jia DM, Shi S, Yang X, Liu Q, et al. tPA mobilizes immune cells that exacerbate hemorrhagic transformation in stroke. Circ Res. (2021) 128:62–75. doi: 10.1161/CIRCRESAHA.120.317596
Ouk T, Potey C, Maestrini I, Petrault M, Mendyk AM, Leys D, et al. Neutrophils in tPA-induced hemorrhagic transformations: Main culprit, accomplice or innocent bystander? Pharmacol Ther. (2019) 194:73–83. doi: 10.1016/j.pharmthera.2018.09.005
Torres LS, Hidalgo A. Neutrophils as drivers of vascular injury in sickle cell disease. Immunol Rev. (2023) 314:302–12. doi: 10.1111/imr.13146
Li W, Terada Y, Tyurina YY, Tyurin VA, Bery AI, Gauthier JM, et al. Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury. Proc Natl Acad Sci USA. (2022) 119:e2111537119. doi: 10.1073/pnas.2111537119
Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. (2018) 18:134–47. doi: 10.1038/nri.2017.105
Lee KH, Kronbichler A, Park DDY, Park YM, Moon H, Kim H, et al. Neutrophil extracellular traps (NETs) in autoimmune diseases: a comprehensive review. Autoimmun Rev. (2017) 16:1160–73. doi: 10.1016/j.autrev.2017.09.012
Zhang H, Wang Y, Qu M, Li W, Wu D, Cata JP, et al. Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis. Clin Transl Med. (2023) 13:e1170. doi: 10.1002/ctm2.1170
Adrover JM, McDowell SAC, He XY, Quail DF, Egeblad M. NETworking with cancer: the bidirectional interplay between cancer and neutrophil extracellular traps. Cancer Cell. (2023) 41:505–26. doi: 10.1016/j.ccell.2023.02.001
Guldolf K, Vandervorst F, Gens R, Ourtani A, Scheinok T, de Raedt S. Neutrophil-to-lymphocyte ratio predicts delirium after stroke. Age Ageing. (2021) 50:1626–32. doi: 10.1093/ageing/afab133
Gong P, Liu Y, Gong Y, Chen G, Zhang X, Wang S, et al. The association of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and lymphocyte to monocyte ratio with post-thrombolysis early neurological outcomes in patients with acute ischemic stroke. J Neuroinflammation. (2021) 18:51. doi: 10.1186/s12974-021-02090-6Chang et al. 10.3389/fneur.2025.1596158 Frontiers in Neurology 15 frontiersin.org
Zhang ZH, Zhang XC, Ni GX. Thrombolysis combined with acupuncture therapy for acute cerebral infarction: a Meta-analysis of randomized controlled trials. Zhen Ci Yan Jiu. (2021) 46:431–8. doi: 10.13702/j.1000-0607.200559
Liu FR, Zhang XC, Cai ZY, Ni GX. Acupuncture regulates autophagic flux to antagonize cerebral ischemic injury in rats. Zhen Ci Yan Jiu. (2022) 47:999–1004. doi: 10.13702/j.1000-0607.20210952
Gu YH, Zhang XC, Xu WT, Zhang A, Zhang ZH, Jiang SY, et al. Effect of acupuncture on neurological function, cerebral infarction volume, thrombolysis time window and cerebral cell apoptosis signaling pathway in cerebral infarction rats. Zhen Ci Yan Jiu. (2020) 45:209–14. doi: 10.13702/j.1000-0607.190635
Zhang Z, Lu T, Li S, Zhao R, Li H, Zhang X, et al. Acupuncture extended the thrombolysis window by suppressing blood-brain barrier disruption and regulating autophagy-apoptosis balance after ischemic stroke. Brain Sci. (2024) 14:399. doi: 10.3390/brainsci14040399
Feng Y, Peng Y, Song X, Wen H, An Y, Tang H, et al. Anopheline mosquitoes are protected against parasite infection by tryptophan catabolism in gut microbiota. Nat Microbiol. (2022) 7:707–15. doi: 10.1038/s41564-022-01099-8
Teunis CJ, Stroes ESG, Boekholdt SM, Wareham NJ, Murphy AJ, Nieuwdorp M, et al. Tryptophan metabolites and incident cardiovascular disease: the EPIC-Norfolk prospective population study. Atherosclerosis. (2023) 387:117344. doi: 10.1016/j.atherosclerosis.2023.117344
Luo H, Guo H, Zhou Y, Fang R, Zhang W, Mei Z. Neutrophil extracellular traps in cerebral ischemia/reperfusion injury: friend and foe. Curr Neuropharmacol. (2023) 21:2079–96. doi: 10.2174/1570159X21666230308090351
Alexeev EE, Dowdell AS, Henen MA, Lanis JM, Lee JS, Cartwright IM, et al. Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage. FASEB J. (2021) 35:e21552. doi: 10.1096/fj.202100027R
Sousa-Neto BP, Cunha FVM, Nunes DB, Gomes BS, Amorim LV, Lopes EM, et al. Anti-inflammatory and antioxidant effects of the indole-derived N-Salicyloyltryptamine on peritonitis and joint disability induced by carrageenan in rodents. Evid Based Complement Alternat Med. (2022) 2022:5524107. doi: 10.1155/2022/5524107
Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. (2002) 71:635–700. doi: 10.1146/annurev.biochem.71.110601.135414
Yuan Q, Yuan Y, Zheng Y, Sheng R, Liu L, Xie F, et al. Anti-cerebral ischemia reperfusion injury of polysaccharides: a review of the mechanisms. Biomed Pharmacother. (2021) 137:111303. doi: 10.1016/j.biopha.2021.111303
Tuo QZ, Zhang ST, Lei P. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications. Med Res Rev. (2022) 42:259–305. doi: 10.1002/med.21817
Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol. (2018) 18:195–203. doi: 10.1038/nri.2017.145
Rodriguez-Carrio J, Lopez P, Suarez A. Endothelial progenitor cells as mediators of the crosstalk between vascular repair and immunity: lessons from systemic autoimmune diseases. Curr Med Chem. (2018) 25:4478–96. doi: 10.2174/0929867324666170428110311
Goncalves A, Su EJ, Muthusamy A, Zeitelhofer M, Torrente D, Nilsson I, et al. Thrombolytic tPA-induced hemorrhagic transformation of ischemic stroke is mediated by PKCbeta phosphorylation of occludin. Blood. (2022) 140:388–400. doi: 10.1182/blood.2021014958
Regard JB, Harrison TJ, Axford J, Axford L, Lee L, Ren X, et al. Discovery of a novel, highly potent and orally bioavailable pyrrolidinone indole series of irreversible myeloperoxidase (MPO) inhibitors. Biochem Pharmacol. (2023) 209:115418. doi: 10.1016/j.bcp.2023.115418
Li L, Cheng SQ, Sun YQ, Yu JB, Huang XX, Dong YF, et al. Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke. Cell Rep. (2023) 42:112617. doi: 10.1016/j.celrep.2023.112617
Dou H, Wang R, Tavallaie M, Xiao T, Olszewska M, Papapetrou EP, et al. Hematopoietic and eosinophil-specific LNK(SH2B3) deficiency promotes eosinophilia and arterial thrombosis. Blood. (2024) 143:1758–72. doi: 10.1182/blood.2023021055
Kuang H, Zhu X, Chen H, Tang H, Zhao H. The immunomodulatory mechanism of acupuncture treatment for ischemic stroke: research progress, prospects, and future direction. Front Immunol. (2024) 15:1319863. doi: 10.3389/fimmu.2024.1319863