Neuroprotective Mechanism of Icariin against Cerebral Ischemic-Reperfusion Injury: A Systematic Review
DOI:
https://doi.org/10.22225/ijbstm.2.1.2025.14-18Keywords:
Icariin, neuroprotective mechanism, cerebral ischemic-reperfusion injuryAbstract
Background: Ischemic stroke has become one of the most life-threatening diseases with high disability and mortality rates. New treatment strategies with neuroprotective functions are urgently needed to treat it. Icariin is a flavonol glycoside that has antioxidant capacity, promote neurite outgrowth and modulate the immune system. This systematic review was conducted to assess and evaluate the efficacy, safety and feasibility of icariin in the treatment of ischemic stroke.
Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. We included predefined inclusion criteria, including: original articles published in the last 10 years and in English. Abstracts, preprints, reviews, articles not published in English and inaccessible full-text articles are excluded. Data extracted from PubMed and ScienceDirect databases using keywords "ischemic stroke“ or ‘”cerebral ischemic-reperfusion injury“ and '"icariin". The JBI critical appraisal tool was used to assess the quality of the data.
Results: From the data obtained, a total of 7 research data were found eligible to review. The results showed that icariin had positive effects in reducing the levels of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumour necrosis factor-alfa (TNF-alfa) as well as maintaining brain cell viability. In addition, icariin either given alone or in combination improves post-ischemic neurological function and reduces infarct volume.
Conclusion: Icariin has demonstrated neuroprotective effects necessary for neuroprotection and neurovascular recovery. In vitro and in vivo studies using Icariin alone or in combination with other modalities have also shown enhanced protection.
References
Agalave, N. M., & Svensson, C. I. (2014). Extracellular High-Mobility Group Box 1 Protein (HMGB1) as a Mediator of Persistent Pain. Molecular Medicine, 20(1), 569–578. https://doi.org/10.2119/molmed.2014.00176
Amruta, N., Rahman, A. A., Pinteaux, E., & Bix, G. (2020). Neuroinflammation and fibrosis in stroke: The good, the bad and the ugly. Journal of Neuroimmunology, 346, 577318. https://doi.org/10.1016/j.jneuroim.2020.577318
Andrabi, S. S., Parvez, S., & Tabassum, H. (2020). Ischemic stroke and mitochondria: Mechanisms and targets. Protoplasma, 257(2), 335–343. https://doi.org/10.1007/s00709-019-01439-2
Barker, T. H., Habibi, N., Aromataris, E., Stone, J. C., Leonardi-Bee, J., Sears, K., Hasanoff, S., Klugar, M., Tufanaru, C., Moola, S., & Munn, Z. (2024). The revised JBI critical appraisal tool for the assessment of risk of bias for quasi-experimental studies. JBI Evidence Synthesis, 22(3), 378–388. https://doi.org/10.11124/JBIES-23-00268
Boyko, M., Zlotnik, A., Gruenbaum, B. F., Gruenbaum, S. E., Ohayon, S., Goldsmith, T., Kotz, R., Leibowitz, A., Sheiner, E., Shapira, Y., & Teichberg, V. I. (2010). An experimental model of focal ischemia using an internal carotid artery approach. Journal of Neuroscience Methods, 193(2), 246–253. https://doi.org/10.1016/j.jneumeth.2010.08.026
Chen, S., Zou, R., Si, J., Shi, Q., Zhang, L., Kang, L., Ni, J., & Sha, D. (2024). Icariin inhibits apoptosis in OGD-induced neurons by regulating M2 pyruvate kinase. IBRO Neuroscience Reports, 16, 535–541. https://doi.org/10.1016/j.ibneur.2024.04.005
Dai, M., Chen, B., Wang, X., Gao, C., & Yu, H. (2021). Icariin enhance mild hypothermia-induced neuroprotection via inhibiting the activation of NF-kB in experimental ischemic stroke. Metabolic Brain Disease, 36(7), 1779–1790. https://doi.org/10.1007/s11011-021-00731-6
Gong, M., Han, B., Wang, S., Liang, S., & Zou, Z. (2016). Icariin reverses corticosterone-induced depression-like behavior, decrease in hippocampal brain-derived neurotrophic factor (BDNF) and metabolic network disturbances revealed by NMR-based metabonomics in rats. Journal of Pharmaceutical and Biomedical Analysis, 123, 63–73. https://doi.org/10.1016/j.jpba.2016.02.001
Gu, Y., Zhou, C., Piao, Z., Yuan, H., Jiang, H., Wei, H., Zhou, Y., Nan, G., & Ji, X. (2022). Cerebral edema after ischemic stroke: Pathophysiology and underlying mechanisms. Frontiers in Neuroscience, 16, 988283. https://doi.org/10.3389/fnins.2022.988283
Hui, C., Tadi, P., Khan Suheb, M. Z., & Patti, L. (2025). Ischemic Stroke. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK499997/
Jian, Z., Liu, R., Zhu, X., Smerin, D., Zhong, Y., Gu, L., Fang, W., & Xiong, X. (2019). The Involvement and Therapy Target of Immune Cells After Ischemic Stroke. Frontiers in Immunology, 10, 2167. https://doi.org/10.3389/fimmu.2019.02167
Kawakita, F., Kanamaru, H., Asada, R., & Suzuki, H. (2019). Potential roles of matricellular proteins in stroke. Experimental Neurology, 322, 113057. https://doi.org/10.1016/j.expneurol.2019.113057
Li, C., Li, Q., Mei, Q., & Lu, T. (2015). Pharmacological effects and pharmacokinetic properties of icariin, the major bioactive component in Herba Epimedii. Life Sciences, 126, 57–68. https://doi.org/10.1016/j.lfs.2015.01.006
Liu, D., Ye, Y., Xu, L., Yuan, W., & Zhang, Q. (2018). Icariin and mesenchymal stem cells synergistically promote angiogenesis and neurogenesis after cerebral ischemia via PI3K and ERK1/2 pathways. Biomedicine & Pharmacotherapy, 108, 663–669. https://doi.org/10.1016/j.biopha.2018.09.071
Mo, Z., Liao, Y., Zheng, J., & Li, W. (2020). Icariin protects neurons from endoplasmic reticulum stress-induced apoptosis after OGD/R injury via suppressing IRE1a-XBP1 signaling pathway. Life Sciences, 255, 117847. https://doi.org/10.1016/j.lfs.2020.117847
Nakamura, K., & Shichita, T. (2019). Cellular and molecular mechanisms of sterile inflammation in ischaemic stroke. The Journal of Biochemistry, 165(6), 459–464. https://doi.org/10.1093/jb/mvz017
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, n71. https://doi.org/10.1136/bmj.n71
Sedova, P., Brown, R. D., Zvolsky, M., Belaskova, S., Volna, M., Baluchova, J., Bednarik, J., & Mikulik, R. (2021). Incidence of Stroke and Ischemic Stroke Subtypes: A Community-Based Study in Brno, Czech Republic. Cerebrovascular Diseases, 50(1), 54–61. https://doi.org/10.1159/000512180
Su, L., Zhang, R., Chen, Y., Zhu, Z., & Ma, C. (2017). Raf Kinase Inhibitor Protein Attenuates Ischemic-Induced Microglia Cell Apoptosis and Activation Through NF-kB Pathway. Cellular Physiology and Biochemistry, 41(3), 1125–1134. https://doi.org/10.1159/000464119
Tadi, P., & Lui, F. (2025). Acute Stroke. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK535369/
Tasoulis, M., & Douzinas, E. E. (2016). Hypoxemic reperfusion of ischemic states: An alternative approach for the attenuation of oxidative stress mediated reperfusion injury. Journal of Biomedical Science, 23(1), 7. https://doi.org/10.1186/s12929-016-0220-0
Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Delling, F. N., Djousse, L., Elkind, M. S. V., Ferguson, J. F., Fornage, M., Khan, S. S., Kissela, B. M., Knutson, K. L., Kwan, T. W., Lackland, D. T., … On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. (2020). Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association. Circulation, 141(9). https://doi.org/10.1161/CIR.0000000000000757
Wang, S., Ma, J., Zeng, Y., Zhou, G., Wang, Y., Zhou, W., Sun, X., & Wu, M. (2021). Icariin, an Up-and-Coming Bioactive Compound Against Neurological Diseases: Network Pharmacology-Based Study and Literature Review. Drug Design, Development and Therapy, Volume 15, 3619–3641. https://doi.org/10.2147/DDDT.S310686
Wu, C.-T., Chen, M.-C., Liu, S.-H., Yang, T.-H., Long, L.-H., Guan, S.-S., & Chen, C.-M. (2021). Bioactive Flavonoids Icaritin and Icariin Protect against Cerebral Ischemia–Reperfusion-Associated Apoptosis and Extracellular Matrix Accumulation in an Ischemic Stroke Mouse Model. Biomedicines, 9(11), 1719. https://doi.org/10.3390/biomedicines9111719
Xie, W., Zhu, T., Zhou, P., Xu, H., Meng, X., Ding, T., Nan, F., Sun, G., & Sun, X. (2020). Notoginseng Leaf Triterpenes Ameliorates OGD/R-Induced Neuronal Injury via SIRT1/2/3-Foxo3a-MnSOD/PGC-1a Signaling Pathways Mediated by the NAMPT-NAD Pathway. Oxidative Medicine and Cellular Longevity, 2020, 1–15. https://doi.org/10.1155/2020/7308386
Xiong, D., Deng, Y., Huang, B., Yin, C., Liu, B., Shi, J., & Gong, Q. (2016). Icariin attenuates cerebral ischemia–reperfusion injury through inhibition of inflammatory response mediated by NF-kB, PPARa and PPARy in rats. International Immunopharmacology, 30, 157–162. https://doi.org/10.1016/j.intimp.2015.11.035
Xu, Y., Lu, X., Zhang, L., Wang, L., Zhang, G., Yao, J., & Sun, C. (2021). Icaritin activates Nrf2/Keap1 signaling to protect neuronal cells from oxidative stress. Chemical Biology & Drug Design, 97(1), 111–120. https://doi.org/10.1111/cbdd.13765
Zhou, Z., Li, W., Ni, L., Wang, T., Huang, Y., Yu, Y., Hu, M., Liu, Y., Wang, J., Huang, X., & Wang, Y. (2024). Icariin improves oxidative stress injury during ischemic stroke via inhibiting mPTP opening. Molecular Medicine, 30(1), 77. https://doi.org/10.1186/s10020-024-00847-2
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Diana Yuswanti Putri, Yuyun Yueniwati, Sri Utami, Nirmala Halid, Husnul Khotimah
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
