Main Article Content
Abstract
Background: Ischemic stroke is an acute neurological injury resulting from focal damage to the central nervous system due to vascular obstruction and subsequent decrease in cerebral blood flow. Numerous animal models of ischemic stroke have been established to investigate its mechanism, pathophysiology, and risk factors. The animal model of ischemic stroke includes a global ischemia model and a focal ischemia model. This article describes various parameters, including hematological, biochemical, cytological, histological, and molecular factors, along with diverse biomarkers, that may support research in the development of novel, safer, and more effective therapeutic agents for ischemic stroke using animal models.
Objective: This research seeks to determine the appropriate test animal model and parameters for ischemic stroke experiments.
Method: A complete literature search was conducted across multiple databases, including NCBI, PubMed, and additional sources.
Results: According to reference studies, the animal model test in the ischemic stroke experiment comprised a focal ischemia model and a global ischemic model. The focal ischemic model is more pertinent to ischemic stroke in humans compared to the global ischemic model. In addition, focal ischemic models, including Middle Cerebral Artery Occlusion (MCAO), have been utilized in over 40% of 2,582 nerve protection trials. The wide variety of test animal models possesses distinct advantages and disadvantages, making it crucial to select the appropriate model. The parameters of ischemic stroke, including hematology, biochemistry, cytology, histology, and molecular analysis, together with their biomarkers, can help in identifying the incidence of ischemic stroke in test animals.
Conclusion: The focused ischemia model is a more pertinent animal model for ischemic stroke in relation to humans than the global ischemic model. Parameters utilized for the identification of ischemic stroke encompass hematology, biochemistry, cytology, histology, and molecular biology.
Keywords
Article Details
Copyright (c) 2025 Lisa Agustina Botutihe, Rizka Safira, Kintoko

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References
- Alam, S. M., Md Arifuzzaman, -, Rahman, H., Rahman, H. Z., & Islam, M. R. (2014). Ischemic Stroke and Serum CPK: A Review. Bangladesh Journal of Neuroscience, 30(2), 112–116. https://doi.org/10.3329/bjn.v30i2.57395
- Alkireidmi, M. A., Al-Abbasi, F. A., Mehanna, M. G., & Moselhy, S. S. (2018). Biochemical markers as diagnostic/prognostic indicators for ischemic disease. African Health Sciences, 18(2), 287–294. https://doi.org/10.4314/ahs.v18i2.13
- 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
- Ansari, S., Azari, H., Caldwell, K. J., Regenhardt, R. W., Hedna, V. S., Waters, M. F., Hoh, B. L., & Mecca, A. P. (2013). Endothelin-1 induced middle cerebral artery occlusion model for ischemic stroke with laser Doppler flowmetry guidance in rat. Journal of Visualized Experiments : JoVE, 72, 1–6. https://doi.org/10.3791/50014
- Bansal, S., Sangha, K. S., & Khatri, P. (2013). Drug treatment of acute ischemic stroke. American Journal of Cardiovascular Drugs, 13(1), 57–69. https://doi.org/10.1007/s40256-013-0007-6
- Bayat, M., & Haghani, M. (2017). Acute bilateral common carotid arteries occlusion (2VO) alone could not be a proper method for induction of ischemia in rats. Biomedicine and Pharmacotherapy, 96(November), 1557–1558. https://doi.org/10.1016/j.biopha.2017.11.102
- Cai, Q., Xu, G., Liu, J., Wang, L., Deng, G., Liu, J., & Chen, Z. (2016). A modification of intraluminal middle cerebral artery occlusion/reperfusion model for ischemic stroke with laser Doppler flowmetry guidance in mice. Neuropsychiatric Disease and Treatment, 12, 2851–2858. https://doi.org/10.2147/NDT.S118531
- Chen, C. Y., Chen, R. J., & Lee, G. A. (2019). Two-vessel occlusion mouse model of cerebral ischemia-reperfusion. Journal of Visualized Experiments, 2019(145), 4–9. https://doi.org/10.3791/59078
- Cui, R., Iso, H., Yamagishi, K., Saito, I., Kokubo, Y., Inoue, M., & Tsugane, S. (2012). High serum total cholesterol levels is a risk factor of ischemic stroke for general Japanese population: The JPHC study. Atherosclerosis, 221(2), 565–569. https://doi.org/10.1016/j.atherosclerosis.2012.01.013
- Dai, P. M., Huang, H., Zhang, L., He, J., Zhao, X. D., Yang, F. H., Zhao, N., Yang, J. Z., Ge, L. J., Lin, Y., Yu, H. L., & Wang, J. H. (2017). A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys. Scientific Reports, 7(November 2016), 1–12. https://doi.org/10.1038/srep45097
- Dave, K. R., Della-Morte, D., Saul, I., Prado, R., & Perez-Pinzon, M. A. (2013). Ventricular Fibrillation-Induced Cardiac Arrest in the Rat as a Model of Global Cerebral Ischemia. Translational Stroke Research, 4(5), 571–578. https://doi.org/10.1007/s12975-013-0267-0
- Donkel, S. J., Benaddi, B., Dippel, D. W. J., Ten Cate, H., & De Maat, M. P. M. (2019). Prognostic hemostasis biomarkers in acute ischemic stroke: A systematic review. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(3), 360–372. https://doi.org/10.1161/ATVBAHA.118.312102
- Donkor, E. S. (2018). Stroke in the 21st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life. Stroke Research and Treatment, 2018. https://doi.org/10.1155/2018/3238165
- Dotson, A. L., Chen, Y., Zhu, W., Libal, N., Alkayed, N. J., & Offner, H. (2016). Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion. Translational Stroke Research, 7(1), 70–78. https://doi.org/10.1007/s12975-015-0436-4
- Durand, A., Chauveau, F., Cho, T. H., Bolbos, R., Langlois, J. B., Hermitte, L., Wiart, M., Berthezène, Y., & Nighoghossian, N. (2012). Spontaneous Reperfusion after In Situ Thromboembolic Stroke in Mice. PLoS ONE, 7(11). https://doi.org/10.1371/journal.pone.0050083
- Fidaleo, M., Cavallucci, V., & Pani, G. (2017). Nutrients, neurogenesis and brain ageing: From disease mechanisms to therapeutic opportunities. Biochemical Pharmacology, 141, 63–76. https://doi.org/10.1016/j.bcp.2017.05.016
- Fluri, F., Schuhmann, M. K., & Kleinschnitz, C. (2015). Animal models of ischemic stroke and their application in clinical research. Drug Design, Development and Therapy, 9, 3445–3454. https://doi.org/10.2147/DDDT.S56071
- Han, Y., Yuan, M., Guo, Y. S., Shen, X. Y., Gao, Z. K., & Bi, X. (2021). Mechanism of Endoplasmic Reticulum Stress in Cerebral Ischemia. Frontiers in Cellular Neuroscience, 15(August). https://doi.org/10.3389/fncel.2021.704334
- Hermann, D. M., Popa-Wagner, A., Kleinschnitz, C., & Doeppner, T. R. (2019). Animal models of ischemic stroke and their impact on drug discovery. Expert Opinion on Drug Discovery, 14(3), 315–326. https://doi.org/10.1080/17460441.2019.1573984
- Herson, P. S., & Traystman, R. J. (2014). Animal models of stroke: Translational potential at present and in 2050. Future Neurology, 9(5), 541–551. https://doi.org/10.2217/fnl.14.44
- Howells, D. W., Sena, E. S., & Macleod, M. R. (2014). Bringing rigour to translational medicine. Nature Reviews Neurology, 10(1), 37–43. https://doi.org/10.1038/nrneurol.2013.232
- Kim, S. J., Moon, G. J., & Bang, O. Y. (2013). Biomarkers for Stroke Discovering biomarkers for stroke. Journal of Stroke, 15(1), 27–37.
- Kumar, A., Aakriti, & Gupta, V. (2016). A review on animal models of stroke: An update. Brain Research Bulletin, 122, 35–44. https://doi.org/10.1016/j.brainresbull.2016.02.016
- Li, Y., & Zhang, J. (2021). Animal models of stroke. Animal Models and Experimental Medicine, 4(3), 204–219. https://doi.org/10.1002/ame2.12179
- Liu, L. B., Li, M., Zhuo, W. Y., Zhang, Y. S., & Xu, A. D. (2015). The role of Hs-CRP, D-dimer and fibrinogen in differentiating etiological subtypes of ischemic stroke. PLoS ONE, 10(2), 1–9. https://doi.org/10.1371/journal.pone.0118301
- Liu, F., Lu, J., Manaenko, A., Tang, J., & Hu, Q. (2018). Mitochondria in ischemic stroke: New insight and implications. Aging and Disease, 9(5), 924–937. https://doi.org/10.14336/AD.2017.1126
- Lu, D., Wu, Y., Qu, Y., Shi, F., Hu, J., Gao, B., Wang, B., Gao, G., He, S., & Zhao, T. (2016). A modified method to reduce variable outcomes in a rat model of four-vessel arterial occlusion. Neurological Research, 38(12), 1102–1110. https://doi.org/10.1080/01616412.2016.1249996
- Ma, J., Peng, C., Guo, W., Dong, Y. F., Dong, X. H., Sun, X., & Xie, H. H. (2012). A modified model of middle cerebral artery electrocoagulation in mice. CNS Neuroscience and Therapeutics, 18(9), 796–798. https://doi.org/10.1111/j.1755-5949.2012.00370.x
- Marino, K. M., Silva, E. R., & Windelborn, J. A. (2020). A comparison between chemical and gas hypoxia as models of global ischemia in zebrafish ( Danio rerio ) . Animal Models and Experimental Medicine, 3(3), 256–263. https://doi.org/10.1002/ame2.12132
- McCabe, C., Arroja, M. M., Reid, E., & Macrae, I. M. (2018). Animal models of ischaemic stroke and characterisation of the ischaemic penumbra. Neuropharmacology, 134(September), 169–177. https://doi.org/10.1016/j.neuropharm.2017.09.022
- Muchti, J. E., Anwar, Y., & Aman, A. K. (2019). Levels of protein C, protein S, and anti-thrombin III in acute ischemic stroke patients at Haj Adam Malik Hospital, Medan. Bali Medical Journal, 8(2), 460. https://doi.org/10.15562/bmj.v8i2.1378
- Orset, C., Haelewyn, B., Allan, S. M., Ansar, S., Campos, F., Cho, T. H., Durand, A., El Amki, M., Fatar, M., Garcia-Yébenes, I., Gauberti, M., Grudzenski, S., Lizasoain, I., Lo, E., Macrez, R., Margaill, I., Maysami, S., Meairs, S., Nighoghossian, N., … Vivien, D. (2016). Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis. Stroke, 47(5), 1312–1318. https://doi.org/10.1161/STROKEAHA.116.012238
- Pontarelli, F., Ofengeim, D., Zukin, R., & Jonas, E. (2012). Mouse Transient Global Ischemia Two-Vessel Occlusion Model. Bio-Protocol, 2(18). https://doi.org/10.21769/bioprotoc.262
- Qian, C., Li, P. C., Jiao, Y., Yao, H. H., Chen, Y. C., Yang, J., Ding, J., Yang, X. Y., & Teng, G. J. (2016). Precise characterization of the penumbra revealed by MRI: A modified photothrombotic stroke model study. PLoS ONE, 11(4), 1–13. https://doi.org/10.1371/journal.pone.0153756
- Shash, M. H., Abdelrazek, R., Abdelgeleel, N. M., Ahmed, R. M., & El-baih, A. H. (2021). Validity of neuron-specific enolase as a prognostic tool in acute ischemic stroke in adults at Suez Canal University Hospital. Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 57(1). https://doi.org/10.1186/s41983-021-00268-6
- Soeandy, C., Salmasi, F., Latif, M., Elia, A. J., Suo, N. J., & Henderson, J. T. (2019). Endothelin-1-mediated cerebral ischemia in mice: early cellular events and the role of caspase-3. Apoptosis, 24(7–8), 578–595. https://doi.org/10.1007/s10495-019-01541-z
- Sporns, P. B., Hanning, U., Schwindt, W., Velasco, A., Minnerup, J., Zoubi, T., Heindel, W., Jeibmann, A., & Niederstadt, T. U. (2017). Ischemic Stroke: What Does the Histological Composition Tell Us about the Origin of the Thrombus? Stroke, 48(8), 2206–2210. https://doi.org/10.1161/STROKEAHA.117.016590
- Steliga, A., Kowiański, P., Czuba, E., Waśkow, M., Moryś, J., & Lietzau, G. (2020). Neurovascular Unit as a Source of Ischemic Stroke Biomarkers—Limitations of Experimental Studies and Perspectives for Clinical Application. Translational Stroke Research, 11(4), 553–579. https://doi.org/10.1007/s12975-019-00744-5
- Tarr, D., Graham, D., Roy, L. A., Holmes, W. M., McCabe, C., Mhairi MacRae, I., Muir, K. W., & Dewar, D. (2013). Hyperglycemia accelerates apparent diffusion coefficient-defined lesion growth after focal cerebral ischemia in rats with and without features of metabolic syndrome. Journal of Cerebral Blood Flow and Metabolism, 33(10), 1556–1563. https://doi.org/10.1038/jcbfm.2013.107
- Whiteley, W., Tseng, M. C., & Sandercock, P. (2008). Blood biomarkers in the diagnosis of ischemic stroke: A systematic review. Stroke, 39(10), 2902–2909. https://doi.org/10.1161/STROKEAHA.107.511261
- Xie, J. Q., Lu, Y. P., Sun, H. L., Gao, L. N., Song, P. P., Feng, Z. J., & You, C. G. (2020). Sex Difference of Ribosome in Stroke-Induced Peripheral Immunosuppression by Integrated Bioinformatics Analysis. BioMed Research International, 2020. https://doi.org/10.1155/2020/3650935
- Xu, B., Xiao, A. J., Chen, W., Turlova, E., Liu, R., Barszczyk, A., Sun, C. L. F., Liu, L., Tymianski, M., Feng, Z. P., & Sun, H. S. (2016). Neuroprotective Effects of a PSD-95 Inhibitor in Neonatal Hypoxic-Ischemic Brain Injury. Molecular Neurobiology, 53(9), 5962–5970. https://doi.org/10.1007/s12035-015-9488-4
- Yabuki, Y., Shinoda, Y., Izumi, H., Ikuno, T., Shioda, N., & Fukunaga, K. (2015). Dehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma-1 receptor stimulation. Brain Research, 1622, 102–113. https://doi.org/10.1016/j.brainres.2015.05.006
- Yaghi, S., & Elkind, M. S. V. (2015). Lipids and Cerebrovascular Disease: Research and Practice. Stroke, 46(11), 3322–3328. https://doi.org/10.1161/STROKEAHA.115.011164
- Yang, M., Pan, Y., Li, Z., Yan, H., Zhao, X., Liu, L., Jing, J., Meng, X., Wang, Y., & Wang, Y. (2019). Platelet count predicts adverse clinical outcomes after ischemic stroke or TIA: Subgroup analysis of CNSR II. Frontiers in Neurology, 10(APR), 1–7. https://doi.org/10.3389/fneur.2019.00370
- Yang, Z., Lin, P., Chen, B., Zhang, X., Xiao, W., Wu, S., Huang, C., Feng, D., Zhang, W., & Zhang, J. (2021). Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5). Autophagy, 17(10), 3048–3067. https://doi.org/10.1080/15548627.2020.1851897
- Yueniwati, yuyun P. W. (2015). Deteksi Dini Stroke Iskemik (pp. xxiv–324).
- Zhang, M., Lu, H., Xie, X., Shen, H., Li, X., Zhang, Y., Wu, J., Ni, J., Li, H., & Chen, G. (2020). TMEM175 mediates Lysosomal function and participates in neuronal injury induced by cerebral ischemia-reperfusion. Molecular Brain, 13(1), 1–15. https://doi.org/10.1186/s13041-020-00651-z
- Zhang, R., Bertelsen, L. B., Flø, C., Wang, Y., & Stødkilde-Jørgensen, H. (2016). Establishment and characterization of porcine focal cerebral ischemic model induced by endothelin-1. Neuroscience Letters, 635(1), 1–7. https://doi.org/10.1016/j.neulet.2016.10.036
References
Alam, S. M., Md Arifuzzaman, -, Rahman, H., Rahman, H. Z., & Islam, M. R. (2014). Ischemic Stroke and Serum CPK: A Review. Bangladesh Journal of Neuroscience, 30(2), 112–116. https://doi.org/10.3329/bjn.v30i2.57395
Alkireidmi, M. A., Al-Abbasi, F. A., Mehanna, M. G., & Moselhy, S. S. (2018). Biochemical markers as diagnostic/prognostic indicators for ischemic disease. African Health Sciences, 18(2), 287–294. https://doi.org/10.4314/ahs.v18i2.13
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
Ansari, S., Azari, H., Caldwell, K. J., Regenhardt, R. W., Hedna, V. S., Waters, M. F., Hoh, B. L., & Mecca, A. P. (2013). Endothelin-1 induced middle cerebral artery occlusion model for ischemic stroke with laser Doppler flowmetry guidance in rat. Journal of Visualized Experiments : JoVE, 72, 1–6. https://doi.org/10.3791/50014
Bansal, S., Sangha, K. S., & Khatri, P. (2013). Drug treatment of acute ischemic stroke. American Journal of Cardiovascular Drugs, 13(1), 57–69. https://doi.org/10.1007/s40256-013-0007-6
Bayat, M., & Haghani, M. (2017). Acute bilateral common carotid arteries occlusion (2VO) alone could not be a proper method for induction of ischemia in rats. Biomedicine and Pharmacotherapy, 96(November), 1557–1558. https://doi.org/10.1016/j.biopha.2017.11.102
Cai, Q., Xu, G., Liu, J., Wang, L., Deng, G., Liu, J., & Chen, Z. (2016). A modification of intraluminal middle cerebral artery occlusion/reperfusion model for ischemic stroke with laser Doppler flowmetry guidance in mice. Neuropsychiatric Disease and Treatment, 12, 2851–2858. https://doi.org/10.2147/NDT.S118531
Chen, C. Y., Chen, R. J., & Lee, G. A. (2019). Two-vessel occlusion mouse model of cerebral ischemia-reperfusion. Journal of Visualized Experiments, 2019(145), 4–9. https://doi.org/10.3791/59078
Cui, R., Iso, H., Yamagishi, K., Saito, I., Kokubo, Y., Inoue, M., & Tsugane, S. (2012). High serum total cholesterol levels is a risk factor of ischemic stroke for general Japanese population: The JPHC study. Atherosclerosis, 221(2), 565–569. https://doi.org/10.1016/j.atherosclerosis.2012.01.013
Dai, P. M., Huang, H., Zhang, L., He, J., Zhao, X. D., Yang, F. H., Zhao, N., Yang, J. Z., Ge, L. J., Lin, Y., Yu, H. L., & Wang, J. H. (2017). A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys. Scientific Reports, 7(November 2016), 1–12. https://doi.org/10.1038/srep45097
Dave, K. R., Della-Morte, D., Saul, I., Prado, R., & Perez-Pinzon, M. A. (2013). Ventricular Fibrillation-Induced Cardiac Arrest in the Rat as a Model of Global Cerebral Ischemia. Translational Stroke Research, 4(5), 571–578. https://doi.org/10.1007/s12975-013-0267-0
Donkel, S. J., Benaddi, B., Dippel, D. W. J., Ten Cate, H., & De Maat, M. P. M. (2019). Prognostic hemostasis biomarkers in acute ischemic stroke: A systematic review. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(3), 360–372. https://doi.org/10.1161/ATVBAHA.118.312102
Donkor, E. S. (2018). Stroke in the 21st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life. Stroke Research and Treatment, 2018. https://doi.org/10.1155/2018/3238165
Dotson, A. L., Chen, Y., Zhu, W., Libal, N., Alkayed, N. J., & Offner, H. (2016). Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion. Translational Stroke Research, 7(1), 70–78. https://doi.org/10.1007/s12975-015-0436-4
Durand, A., Chauveau, F., Cho, T. H., Bolbos, R., Langlois, J. B., Hermitte, L., Wiart, M., Berthezène, Y., & Nighoghossian, N. (2012). Spontaneous Reperfusion after In Situ Thromboembolic Stroke in Mice. PLoS ONE, 7(11). https://doi.org/10.1371/journal.pone.0050083
Fidaleo, M., Cavallucci, V., & Pani, G. (2017). Nutrients, neurogenesis and brain ageing: From disease mechanisms to therapeutic opportunities. Biochemical Pharmacology, 141, 63–76. https://doi.org/10.1016/j.bcp.2017.05.016
Fluri, F., Schuhmann, M. K., & Kleinschnitz, C. (2015). Animal models of ischemic stroke and their application in clinical research. Drug Design, Development and Therapy, 9, 3445–3454. https://doi.org/10.2147/DDDT.S56071
Han, Y., Yuan, M., Guo, Y. S., Shen, X. Y., Gao, Z. K., & Bi, X. (2021). Mechanism of Endoplasmic Reticulum Stress in Cerebral Ischemia. Frontiers in Cellular Neuroscience, 15(August). https://doi.org/10.3389/fncel.2021.704334
Hermann, D. M., Popa-Wagner, A., Kleinschnitz, C., & Doeppner, T. R. (2019). Animal models of ischemic stroke and their impact on drug discovery. Expert Opinion on Drug Discovery, 14(3), 315–326. https://doi.org/10.1080/17460441.2019.1573984
Herson, P. S., & Traystman, R. J. (2014). Animal models of stroke: Translational potential at present and in 2050. Future Neurology, 9(5), 541–551. https://doi.org/10.2217/fnl.14.44
Howells, D. W., Sena, E. S., & Macleod, M. R. (2014). Bringing rigour to translational medicine. Nature Reviews Neurology, 10(1), 37–43. https://doi.org/10.1038/nrneurol.2013.232
Kim, S. J., Moon, G. J., & Bang, O. Y. (2013). Biomarkers for Stroke Discovering biomarkers for stroke. Journal of Stroke, 15(1), 27–37.
Kumar, A., Aakriti, & Gupta, V. (2016). A review on animal models of stroke: An update. Brain Research Bulletin, 122, 35–44. https://doi.org/10.1016/j.brainresbull.2016.02.016
Li, Y., & Zhang, J. (2021). Animal models of stroke. Animal Models and Experimental Medicine, 4(3), 204–219. https://doi.org/10.1002/ame2.12179
Liu, L. B., Li, M., Zhuo, W. Y., Zhang, Y. S., & Xu, A. D. (2015). The role of Hs-CRP, D-dimer and fibrinogen in differentiating etiological subtypes of ischemic stroke. PLoS ONE, 10(2), 1–9. https://doi.org/10.1371/journal.pone.0118301
Liu, F., Lu, J., Manaenko, A., Tang, J., & Hu, Q. (2018). Mitochondria in ischemic stroke: New insight and implications. Aging and Disease, 9(5), 924–937. https://doi.org/10.14336/AD.2017.1126
Lu, D., Wu, Y., Qu, Y., Shi, F., Hu, J., Gao, B., Wang, B., Gao, G., He, S., & Zhao, T. (2016). A modified method to reduce variable outcomes in a rat model of four-vessel arterial occlusion. Neurological Research, 38(12), 1102–1110. https://doi.org/10.1080/01616412.2016.1249996
Ma, J., Peng, C., Guo, W., Dong, Y. F., Dong, X. H., Sun, X., & Xie, H. H. (2012). A modified model of middle cerebral artery electrocoagulation in mice. CNS Neuroscience and Therapeutics, 18(9), 796–798. https://doi.org/10.1111/j.1755-5949.2012.00370.x
Marino, K. M., Silva, E. R., & Windelborn, J. A. (2020). A comparison between chemical and gas hypoxia as models of global ischemia in zebrafish ( Danio rerio ) . Animal Models and Experimental Medicine, 3(3), 256–263. https://doi.org/10.1002/ame2.12132
McCabe, C., Arroja, M. M., Reid, E., & Macrae, I. M. (2018). Animal models of ischaemic stroke and characterisation of the ischaemic penumbra. Neuropharmacology, 134(September), 169–177. https://doi.org/10.1016/j.neuropharm.2017.09.022
Muchti, J. E., Anwar, Y., & Aman, A. K. (2019). Levels of protein C, protein S, and anti-thrombin III in acute ischemic stroke patients at Haj Adam Malik Hospital, Medan. Bali Medical Journal, 8(2), 460. https://doi.org/10.15562/bmj.v8i2.1378
Orset, C., Haelewyn, B., Allan, S. M., Ansar, S., Campos, F., Cho, T. H., Durand, A., El Amki, M., Fatar, M., Garcia-Yébenes, I., Gauberti, M., Grudzenski, S., Lizasoain, I., Lo, E., Macrez, R., Margaill, I., Maysami, S., Meairs, S., Nighoghossian, N., … Vivien, D. (2016). Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis. Stroke, 47(5), 1312–1318. https://doi.org/10.1161/STROKEAHA.116.012238
Pontarelli, F., Ofengeim, D., Zukin, R., & Jonas, E. (2012). Mouse Transient Global Ischemia Two-Vessel Occlusion Model. Bio-Protocol, 2(18). https://doi.org/10.21769/bioprotoc.262
Qian, C., Li, P. C., Jiao, Y., Yao, H. H., Chen, Y. C., Yang, J., Ding, J., Yang, X. Y., & Teng, G. J. (2016). Precise characterization of the penumbra revealed by MRI: A modified photothrombotic stroke model study. PLoS ONE, 11(4), 1–13. https://doi.org/10.1371/journal.pone.0153756
Shash, M. H., Abdelrazek, R., Abdelgeleel, N. M., Ahmed, R. M., & El-baih, A. H. (2021). Validity of neuron-specific enolase as a prognostic tool in acute ischemic stroke in adults at Suez Canal University Hospital. Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 57(1). https://doi.org/10.1186/s41983-021-00268-6
Soeandy, C., Salmasi, F., Latif, M., Elia, A. J., Suo, N. J., & Henderson, J. T. (2019). Endothelin-1-mediated cerebral ischemia in mice: early cellular events and the role of caspase-3. Apoptosis, 24(7–8), 578–595. https://doi.org/10.1007/s10495-019-01541-z
Sporns, P. B., Hanning, U., Schwindt, W., Velasco, A., Minnerup, J., Zoubi, T., Heindel, W., Jeibmann, A., & Niederstadt, T. U. (2017). Ischemic Stroke: What Does the Histological Composition Tell Us about the Origin of the Thrombus? Stroke, 48(8), 2206–2210. https://doi.org/10.1161/STROKEAHA.117.016590
Steliga, A., Kowiański, P., Czuba, E., Waśkow, M., Moryś, J., & Lietzau, G. (2020). Neurovascular Unit as a Source of Ischemic Stroke Biomarkers—Limitations of Experimental Studies and Perspectives for Clinical Application. Translational Stroke Research, 11(4), 553–579. https://doi.org/10.1007/s12975-019-00744-5
Tarr, D., Graham, D., Roy, L. A., Holmes, W. M., McCabe, C., Mhairi MacRae, I., Muir, K. W., & Dewar, D. (2013). Hyperglycemia accelerates apparent diffusion coefficient-defined lesion growth after focal cerebral ischemia in rats with and without features of metabolic syndrome. Journal of Cerebral Blood Flow and Metabolism, 33(10), 1556–1563. https://doi.org/10.1038/jcbfm.2013.107
Whiteley, W., Tseng, M. C., & Sandercock, P. (2008). Blood biomarkers in the diagnosis of ischemic stroke: A systematic review. Stroke, 39(10), 2902–2909. https://doi.org/10.1161/STROKEAHA.107.511261
Xie, J. Q., Lu, Y. P., Sun, H. L., Gao, L. N., Song, P. P., Feng, Z. J., & You, C. G. (2020). Sex Difference of Ribosome in Stroke-Induced Peripheral Immunosuppression by Integrated Bioinformatics Analysis. BioMed Research International, 2020. https://doi.org/10.1155/2020/3650935
Xu, B., Xiao, A. J., Chen, W., Turlova, E., Liu, R., Barszczyk, A., Sun, C. L. F., Liu, L., Tymianski, M., Feng, Z. P., & Sun, H. S. (2016). Neuroprotective Effects of a PSD-95 Inhibitor in Neonatal Hypoxic-Ischemic Brain Injury. Molecular Neurobiology, 53(9), 5962–5970. https://doi.org/10.1007/s12035-015-9488-4
Yabuki, Y., Shinoda, Y., Izumi, H., Ikuno, T., Shioda, N., & Fukunaga, K. (2015). Dehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma-1 receptor stimulation. Brain Research, 1622, 102–113. https://doi.org/10.1016/j.brainres.2015.05.006
Yaghi, S., & Elkind, M. S. V. (2015). Lipids and Cerebrovascular Disease: Research and Practice. Stroke, 46(11), 3322–3328. https://doi.org/10.1161/STROKEAHA.115.011164
Yang, M., Pan, Y., Li, Z., Yan, H., Zhao, X., Liu, L., Jing, J., Meng, X., Wang, Y., & Wang, Y. (2019). Platelet count predicts adverse clinical outcomes after ischemic stroke or TIA: Subgroup analysis of CNSR II. Frontiers in Neurology, 10(APR), 1–7. https://doi.org/10.3389/fneur.2019.00370
Yang, Z., Lin, P., Chen, B., Zhang, X., Xiao, W., Wu, S., Huang, C., Feng, D., Zhang, W., & Zhang, J. (2021). Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5). Autophagy, 17(10), 3048–3067. https://doi.org/10.1080/15548627.2020.1851897
Yueniwati, yuyun P. W. (2015). Deteksi Dini Stroke Iskemik (pp. xxiv–324).
Zhang, M., Lu, H., Xie, X., Shen, H., Li, X., Zhang, Y., Wu, J., Ni, J., Li, H., & Chen, G. (2020). TMEM175 mediates Lysosomal function and participates in neuronal injury induced by cerebral ischemia-reperfusion. Molecular Brain, 13(1), 1–15. https://doi.org/10.1186/s13041-020-00651-z
Zhang, R., Bertelsen, L. B., Flø, C., Wang, Y., & Stødkilde-Jørgensen, H. (2016). Establishment and characterization of porcine focal cerebral ischemic model induced by endothelin-1. Neuroscience Letters, 635(1), 1–7. https://doi.org/10.1016/j.neulet.2016.10.036
