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Translating Animal Models of Ischemic Stroke to the Human Condition

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Abstract

Ischemic stroke is a leading cause of death and disability. However, very few neuroprotective agents have shown promise for treatment of ischemic stroke in clinical trials, despite showing efficacy in many successful preclinical studies. This may be attributed, at least in part, to the incongruency between experimental animal stroke models used in preclinical studies and the manifestation of ischemic stroke in humans. Most often the human population selected for clinical trials are more diverse than the experimental model used in a preclinical study. For successful translation, it is critical to develop clinical trial designs that match the experimental animal model used in the preclinical study. This review aims to provide a comprehensive summary of commonly used animal models with clear correlates between rodent models used to study ischemic stroke and the clinical stroke pathologies with which they most closely align. By improving the correlation between preclinical studies and clinical trials, new neuroprotective agents and stroke therapies may be more accurately and efficiently identified.

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References

  1. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378:11–21.

    Article  PubMed  Google Scholar 

  2. Berkhemer OA, Fransen PSS, Beumer D, Van Den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–20.

    Article  PubMed  Google Scholar 

  3. Hacke W, Kaste M, Fieschl C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA J Am Med Assoc. 1995;274:1017–25.

    Article  CAS  Google Scholar 

  4. The National Institute of Neurological Disorder and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM. 1995;333:1581–7.

    Article  Google Scholar 

  5. Fraser JF. Standardisation of research strategies in acute ischaemic stroke. Lancet Neurol [Internet] Ltd. 2016;15:784–5. https://doi.org/10.1016/S1474-4422(16)30080-1.

    Article  Google Scholar 

  6. Sommer CJ. Ischemic stroke: experimental models and reality. Acta Neuropathol Berlin Heidelberg. 2017;133:245–61.

    Article  Google Scholar 

  7. Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx. 2005;2:396–409.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:2064–89.

    Article  PubMed  Google Scholar 

  9. Sohrabji F, Park MJ, Mahnke A. Sex differences in stroke therapies. J Neurosci Res. 2017;95:681–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Zhang H, Lin S, Chen X, Gu L, Zhu X, Zhang Y, et al. The effect of age, sex and strains on the performance and outcome in animal models of stroke. Neurochem Int. 2019;127:2–11. https://doi.org/10.1016/j.neuint.2018.10.005 ([Internet]. Elsevier).

    Article  PubMed  CAS  Google Scholar 

  11. Messmer SJ, Fraser JF, Pennypacker KR, Roberts JM. Method of intra-arterial drug administration in a rat: sex based optimization of infusion rate. J Neurosci Methods [Internet]. Elsevier B.V.; 2021;357:109178. Available from:https://doi.org/10.1016/j.jneumeth.2021.109178

  12. Lakomkin N, Dhamoon M, Carroll K, Singh IP, Tuhrim S, Lee J, et al. Prevalence of large vessel occlusion in patients presenting with acute ischemic stroke: a 10-year systematic review of the literature. J Neurointerv Surg. 2019;11:241–5.

    Article  PubMed  Google Scholar 

  13. Rennert RC, Wali AR, Steinberg JA, Santiago-Dieppa DR, Olson SE, Pannell JS, et al. Epidemiology, natural history, and clinical presentation of large vessel ischemic stroke. Neurosurgery. 2019;85:S4-8.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dabus G, Linfante I. 2012 The natural history of acute ischemic stroke due to intracranial large-vessel occlusion: what do we know? Tech Vasc Interv Radiol [Internet]. Elsevier Inc.;;15:2–4. Available from: https://doi.org/10.1053/j.tvir.2011.12.003

  15. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6:215–22.

    Article  PubMed  Google Scholar 

  16. Brouns R, Deyn De, pp. The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg. 2009;111:483–95.

    Article  PubMed  CAS  Google Scholar 

  17. Koizumi J, Yoshida Y, Nakazawa T, Ooneda G. Experimental studies of ischemic brain edema: 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Japanese J Stroke. 1986;8:83–94.

    Article  Google Scholar 

  18. Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20:84–91.

    Article  PubMed  CAS  Google Scholar 

  19. McBride DW, Zhang JH. Precision stroke animal models: the permanent MCAO model should be the primary model, not transient MCAO. Transl Stroke Res. 2017;8:397–404.

    Article  Google Scholar 

  20. Gubskiy IL, Namestnikova DD, Cherkashova EA, Chekhonin VP, Baklaushev VP, Gubsky LV, et al. MRI guiding of the middle cerebral artery occlusion in rats aimed to improve stroke modeling. Transl Stroke Res Translational Stroke Research. 2018;9:417–25.

    Article  PubMed  CAS  Google Scholar 

  21. Olsen TSØJ, Skriver EB, Herning M. Cause of cerebral infarction in the carotid territory. Its relation to the size and the location of the infarct and to the underlying vascular lesion. Stroke. 1985;16:459–66.

    Article  PubMed  CAS  Google Scholar 

  22. Li F, Omae T, Fisher M. Spontaneous hyperthermia and its mechanism in the intraluminal suture middle cerebral artery occlusion model of rats. Stroke. 1999;30:2464–71.

    Article  PubMed  CAS  Google Scholar 

  23. Doerfler A, Forsting M, Reith W, Staff C, Heiland S, Schäbitz WR, et al. Decompressive craniectomy in a rat model of “malignant” cerebral hemispheric stroke: experimental support for an aggressive therapeutic approach. J Neurosurg. 1996;85:853–9.

    Article  PubMed  CAS  Google Scholar 

  24. Messmer SJ, Salmeron KE, Frank JA, McLouth CJ, Lukins DE, Hammond TC, et al. Extended middle cerebral artery occlusion (MCAO) model to mirror stroke patients undergoing thrombectomy. Transl Stroke Res [Internet]. Springer US; 2021; Available from: https://doi.org/10.1007/s12975-021-00936-y

  25. Kassem-Moussa H, Graffagnino C. Nonocclusion and spontaneous recanalization rates in acute ischemic stroke. Arch Neurol. 2002;59:1870.

    Article  PubMed  Google Scholar 

  26. Zanette EM, Roberti C, Mancini G, Pozzilli C, Bragoni M, Toni D. Spontaneous middle cerebral artery reperfusion in ischemic stroke: A follow-up study with transcranial Doppler. Stroke. 1995;26:430–3.

    Article  PubMed  CAS  Google Scholar 

  27. Jadhav AP, Aghaebrahim A, Jankowitz BT, Haussen DC, Budzik RF, Bonafe A, et al. Benefit of endovascular thrombectomy by mode of onset: secondary analysis of the DAWN trial. Stroke. 2019;50:3141–6.

    Article  PubMed  Google Scholar 

  28. Kudo M, Aoyama A, Ichimori S, Fukunaga N. An animal model of cerebral infarction. Homologous blood clot emboli in rats. Stroke. 1982;13:505–8.

    Article  PubMed  CAS  Google Scholar 

  29. Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, et al. 2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack; A guideline from the American Heart Association/American Stroke Association. Stroke. 2021.

  30. Orset C, Macrez R, Young AR, Panthou D, Angles-Cano E, Maubert E, et al. Mouse model of in situ thromboembolic stroke and reperfusion. Stroke. 2007;38:2771–8.

    Article  PubMed  Google Scholar 

  31. Hossmann KA. Cerebral ischemia: models, methods and outcomes. Neuropharmacology. 2008;55:257–70.

    Article  PubMed  CAS  Google Scholar 

  32. García-Yébenes I, Sobrado M, Zarruk JG, Castellanos M, De La Ossa NP, Dávalos A, et al. A mouse model of hemorrhagic transformation by delayed tissue plasminogen activator administration after in situ thromboembolic stroke. Stroke. 2011;42:196–203.

    Article  PubMed  Google Scholar 

  33. Won S, Lee JH, Wali B, Stein DG, Sayeed I. Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: involvement of the VEGF-MMP pathway. J Cereb Blood Flow Metab [Internet]. Nature Publishing Group; 2014;34:72–80. Available from: https://doi.org/10.1038/jcbfm.2013.163

  34. Robinson R, Shoemaker W, Schlumpf M, Valk T, Bloom F. Effect of experimental cerebral infarction in rat brain on catecholamines and behavior. Nature. 1975;255:332–4.

    Article  PubMed  CAS  Google Scholar 

  35. Tamura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischaemia in the rat: I. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1981;1:53–60.

    Article  PubMed  CAS  Google Scholar 

  36. Brint S, Jacewicz M, Kiessling M, Tanabe J, Pulsinelli W. Focal brain ischemia in the rat: methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. J Cereb Blood Flow Metab. 1988;8:474–85.

    Article  PubMed  CAS  Google Scholar 

  37. Chen ST, Hsu CY, Hogan EL, Maricq H, Balentine JD. A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction. Stroke. 1986;17:738–43.

    Article  PubMed  CAS  Google Scholar 

  38. Fluri F, Schuhmann MK, Kleinschnitz C. Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther. 2015;9:3445–54.

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Uesugi M, Kasuya Y, Hayashi K, Goto K. SB209670, a potent endothelin receptor antagonist, prevents or delays axonal degeneration after spinal cord injury. Brain Res. 1998;786:235–9.

    Article  PubMed  CAS  Google Scholar 

  40. Watson B, Dietrich W, Busto R, Wachtel M, Ginsberg M. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985;17:497–504.

    Article  PubMed  CAS  Google Scholar 

  41. Uzdensky AB. Photothrombotic stroke as a model of ischemic stroke. Transl Stroke Res Translational Stroke Research. 2018;9:437–51.

    Article  PubMed  Google Scholar 

  42. Lu H, Li Y, Yuan L, Li H, Lu X, Tong S. Induction and imaging of photothrombotic stroke in conscious and freely moving rats. J Biomed Opt. 2014;19:1.

    Article  CAS  Google Scholar 

  43. Yu CL, Zhou H, Chai AP, Yang YX, Mao RR, Xu L. Whole-scale neurobehavioral assessments of photothrombotic ischemia in freely moving mice. J Neurosci Methods. 2015;239:100–7. https://doi.org/10.1016/j.jneumeth.2014.10.004 ([Internet]. Elsevier B.V).

    Article  PubMed  Google Scholar 

  44. Liu NW, Ke CC, Zhao Y, Chen YA, Chan KC, Tan DTW, et al. Evolutional characterization of photochemically induced stroke in rats: a multimodality imaging and molecular biological study. Transl Stroke Res Translational Stroke Research. 2017;8:244–56.

    Article  PubMed  CAS  Google Scholar 

  45. Sun YY, Kuo YM, Chen HR, Short-Miller JC, Smucker MR, Kuan CY. A murine photothrombotic stroke model with an increased fibrin content and improved responses to tPA-lytic treatment. Blood Adv. 2020;4:1222–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Karatas H, Erdener SE, Gursoy-Ozdemir Y, Gurer G, Soylemezoglu F, Dunn AK, et al. Thrombotic distal middle cerebral artery occlusion produced by topical FeCl3 application: a novel model suitable for intravital microscopy and thrombolysis studies. J Cereb Blood Flow Metab [Internet]. Nature Publishing Group; 2011;31:1452–60. Available from: https://doi.org/10.1038/jcbfm.2011.8.

  47. Syeara N, Alamri FF, Jayaraman S, Lee P, Karamyan ST, Arumugam TV, et al. Motor deficit in the mouse ferric chloride-induced distal middle cerebral artery occlusion model of stroke. Behav Brain Res. 2020;380:112418. https://doi.org/10.1016/j.bbr.2019.112418 ([Internet]. Elsevier).

    Article  PubMed  CAS  Google Scholar 

  48. Gerriets T, Li F, Silva MD, Meng X, Brevard M, Sotak CH, et al. The macrosphere model: evaluation of a new stroke model for permanent middle cerebral artery occlusion in rats. J Neurosci Methods. 2003;122:201–11.

    Article  PubMed  Google Scholar 

  49. Mayzel-Oreg O, Omae T, Kazemi M, Li F, Fisher M, Cohen Y, et al. Microsphere-induced embolic stroke: an MRI study. Magn Reson Med. 2004;51:1232–8.

    Article  PubMed  Google Scholar 

  50. Walberer M, Rueger MA. The macrosphere model—an embolic stroke model for studying the pathophysiology of focal cerebral ischemia in a translational approach. Ann Transl Med. 2015;3.

  51. Jin Y, Shi P, Wang Y, Li J, Zhang J, Zhao X, et al. Precise control of embolic stroke with magnetized red blood cells in mice. Commun Biol. 2022;5:1–12.

    Article  CAS  Google Scholar 

  52. Jia JM, Peng C, Wang Y, Zheng J, Ge WP. Control of occlusion of middle cerebral artery in perinatal and neonatal mice with magnetic force. Mol Brain Molecular Brain. 2018;11:1–10.

    Google Scholar 

  53. Sozmen EG, Hinman JD, Carmichael ST. Models that matter: white matter stroke models. Neurotherapeutics. 2012;9:349–58.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Nunez S, Doroudchi MM, Gleichman AJ, Ng KL, Llorente IL, Sozmen EG, et al. A versatile murine model of subcortical white matter stroke for the study of axonal degeneration and white matter neurobiology. J Vis Exp. 2016;2016:1–7.

    Google Scholar 

  55. Willmot M, Gray L, Gibson C, Murphy S, Bath PMW. A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide - Biol Chem. 2005;12:141–9.

    Article  CAS  Google Scholar 

  56. Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J. 1963;27:282–93.

    Article  PubMed  CAS  Google Scholar 

  57. Bailey EL, Smith C, Sudlow CLM, Wardlaw JM. Is the spontaneously hypertensive stroke prone rat a pertinent model of sub cortical ischemic stroke? A systematic review Int J Stroke. 2011;6:434–44.

    Article  PubMed  Google Scholar 

  58. Bailey EL, Mcculloch J, Sudlow C, Wardlaw JM. Potential animal models of lacunar stroke: a systematic review. Stroke. 2009;40.

  59. Hainsworth AH, Markus HS. Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J Cereb Blood Flow Metab. 2008;28:1877–91.

    Article  PubMed  Google Scholar 

  60. Henninger N, Eberius KH, Sicard KM, Kollmar R, Sommer C, Schwab S, et al. A new model of thromboembolic stroke in the posterior circulation of the rat. J Neurosci Methods. 2006;156:1–9.

    Article  PubMed  Google Scholar 

  61. Luo M, Tang X, Zhu J, Qiu Z, Jiang Y. Establishment of acute pontine infarction in rats by electrical stimulation. J Vis Exp. 2020

  62. Oliveira-Ferreira AI, Major S, Przesdzing I, Kang EJ, Dreier JP. Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia. J Cereb Blood Flow Metab. 2020;40:1274–89.

    Article  PubMed  CAS  Google Scholar 

  63. Asai Y, Umemura K, Kohno Y, Uematsu T, Nakashima M. An animal model for hearing disturbance due to inner ear ischemia: photochemically induced thrombotic occlusion of the rat anterior inferior cerebellar artery. Eur Arch Otorhinolaryngol. 1993;250:292–6.

    Article  PubMed  CAS  Google Scholar 

  64. Ito A, Fujimura M, Niizuma K, Kanoke A, Sakata H, Morita-Fujimura Y, et al. Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. Brain Res. 2015;1594:310–20. https://doi.org/10.1016/j.brainres.2014.11.014 ([Internet]. Elsevier).

    Article  PubMed  CAS  Google Scholar 

  65. Roberts JM, Maniskas ME, Fraser JF, Bix GJ. Internal carotid artery stenosis: a novel surgical model for moyamoya syndrome. PLoS ONE. 2018;13:1–10.

    Article  Google Scholar 

  66. Sonobe S, Fujimura M, Niizuma K, Fujimura T, Furudate S, Nishijima Y, et al. Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. NeuroReport. 2014;25:1442–6.

    Article  PubMed  CAS  Google Scholar 

  67. Hattori Y, Kitamura A, Nagatsuka K, Ihara M. A novel mouse model of ischemic carotid artery disease. PLoS ONE. 2014;9:1–7.

    Article  Google Scholar 

  68. Hill MD, Goyal M, Menon BK, Nogueira RG, McTaggart RA, Al E. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet. 2020;395:878–87.

    Article  PubMed  CAS  Google Scholar 

  69. Grupke S, Hall J, Dobbs M, Bix GJ, Fraser JF. Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: from review to preview. Clin Neurol Neurosurg. 2015;129:1–9. https://doi.org/10.1016/j.clineuro.2014.11.013 ([Internet]. Elsevier B.V.).

    Article  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the University of Kentucky Medical Center Library for their help and support.

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Authors and Affiliations

  1. Department of Radiology, University of Kentucky, Lexington, KY, USA

    Abhijith V. Matur & Justin F. Fraser

  2. Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    Eduardo Candelario-Jalil

  3. Department of Neurology and Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Surojit Paul

  4. Department of Foundational Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, MI, USA

    Vardan T. Karamyan

  5. Department of Neurology, University of Kentucky, Lexington, KY, USA

    Jessica D. Lee, Keith Pennypacker & Justin F. Fraser

  6. Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, KY, USA

    Keith Pennypacker & Justin F. Fraser

  7. Department of Neuroscience, University of Kentucky, Lexington, KY, USA

    Justin F. Fraser

  8. Department of Neurological Surgery, University of Kentucky, Lexington, KY, USA

    Justin F. Fraser

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  1. Abhijith V. Matur
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Contributions

E. C. J., V. K., S. P., J. L., J. F. F., and K. P. conceptualized the manuscript. A. V. M. drafted the manuscript and conducted the literature search. K. P. and J. F. F. obtained the figures used. All authors critically revised and reviewed the manuscript.

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Correspondence to Abhijith V. Matur.

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All animal experiments depicted in the figures of this article were undertaken in accordance with institutional review board approval and with institutional animal care and use committee approval and oversight. Any images of human patients have been completely de-identified to respect their privacy and in accordance with the Health Insurance Portability and Accountability Act. If this manuscript were to be published, the included patients cannot be identified based on the figures.

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Matur, A.V., Candelario-Jalil, E., Paul, S. et al. Translating Animal Models of Ischemic Stroke to the Human Condition. Transl. Stroke Res. 14, 842–853 (2023). https://doi.org/10.1007/s12975-022-01082-9

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