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Correcting for Brain Swelling’s Effects on Infarct Volume Calculation After Middle Cerebral Artery Occlusion in Rats

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Abstract

Evaluating infarct volume is the primary outcome for experimental ischemic stroke studies and is a major factor in determining translation of a drug into clinical trials. Numerous algorithms are available for evaluating this critical value, but a major limitation of current algorithms is that brain swelling is not appropriately considered. The model by Lin et al. is widely used, but overestimates swelling within the infarction, yielding infarct volumes which do not reflect the true infarct size. Herein, a new infarct volume algorithm is developed to minimize the effects of both peri-infarct and infarct core swelling on infarct volume measurement. 2,3,5-Triphenyl-2H-tetrazolium chloride-stained brain tissue of adult rats subjected to middle cerebral artery occlusion was used for infarct volume analysis. When both peri-infarct swelling and infarction core swelling are removed from infarct volume calculations, such as accomplished by our algorithm, larger infarct volumes are estimated than those of Lin et al.’s algorithm. Furthermore, the infarct volume difference between the two algorithms is the greatest for small infarcts (<10 % of brain volume) when peri-infarct swelling is the greatest. Finally, using data from four published studies, our algorithm is compared to Lin et al.’s algorithm. Our algorithm offers a more reliable estimation of the infarct volume after ischemic brain injury, and thus may provide the foundation for comparing infarct volumes between experimental studies and standardizing infarct volume quantification to aid in the selection of the best candidates for clinical trials.

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References

  1. Dirnagl U, Fisher M. International, multicenter randomized preclinical trials in translational stroke research: it’s time to act. J Cereb Blood Flow Metab. 2012;32(6):933–5.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Schabitz WR, Fisher M. Perspectives on neuroprotective stroke therapy. Biochem Soc Trans. 2006;34(6):1271–6.

    Article  PubMed  Google Scholar 

  3. Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM. Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke. 1986;17(6):1304–8.

    Article  CAS  PubMed  Google Scholar 

  4. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17(3):472–6.

    Article  CAS  PubMed  Google Scholar 

  5. Carano RA, Li F, Irie K, Helmer KG, Silva MD, Fisher M, et al. Multispectral analysis of the temporal evolution of cerebral ischemia in the rat brain. J Magn Reson Imaging. 2000;12(6):842–58.

    Article  CAS  PubMed  Google Scholar 

  6. Duverger D, MacKenzie ET. The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age. J Cereb Blood Flow Metab. 1988;8(4):449–61.

    Article  CAS  PubMed  Google Scholar 

  7. Hoff JT, Nishimura M, Newfield P. Pentobarbital protection from cerebral infarction without suppression of edema. Stroke. 1982;13(5):623–8.

    Article  CAS  PubMed  Google Scholar 

  8. Jiang Q, Chopp M, Zhang ZG, Knight RA, Jacobs M, Windham JP, et al. The temporal evolution of MRI tissue signatures after transient middle cerebral artery occlusion in rat. J Neurol Sci. 1997;145(1):15–23.

    Article  CAS  PubMed  Google Scholar 

  9. Jones PG, Coyle P. Microcomputer assisted lesion size measurements in spontaneously hypertensive stroke-prone rats. J Electrophysiol Tech. 1984;11:71–8.

    Google Scholar 

  10. Lundy EF, Solik BS, Frank RS, Lacy PS, Combs DJ, Zelenock GB, et al. Morphometric evaluation of brain infarcts in rats and gerbils. J Pharmacol Methods. 1986;16(3):201–14.

    Article  CAS  PubMed  Google Scholar 

  11. Nemoto E, Mendez O, Kerr M, Firlik A, Stevenson K, Jovin T, et al. CT density changes with rapid onset acute, severe, focal cerebral ischemia in monkeys. Translat Stroke Res. 2012;3(3):369–74.

    Article  Google Scholar 

  12. Lin TN, He YY, Wu G, Khan M, Hsu CY. Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke. 1993;24(1):117–21.

    Article  CAS  PubMed  Google Scholar 

  13. Khanna A, Kahle KT, Walcott BP, Gerzanich V, Simard JM. Disruption of ion homeostasis in the neurogliovascular unit underlies the pathogenesis of ischemic cerebral edema. Translat Stroke Res. 2014;5(1):3–16.

    Article  CAS  Google Scholar 

  14. Seifert HA, Pennypacker KR. Molecular and cellular immune responses to ischemic brain injury. Translat Stroke Res. 2014;5(5):543–53.

    Article  CAS  Google Scholar 

  15. Song M, Yu SP. Ionic regulation of cell volume changes and cell death after ischemic stroke. Translat Stroke Res. 2014;5(1):17–27.

    Article  CAS  Google Scholar 

  16. Swanson RA, Sharp FR. Infarct measurement methodology. J Cereb Blood Flow Metab. 1994;14(4):697–8.

    Article  CAS  PubMed  Google Scholar 

  17. Kawamura S, Yasui N, Shirasawa M, Fukasawa H. Rat middle cerebral artery occlusion using an intraluminal thread technique. Acta Neurochir. 1991;109(3–4):126–32.

    Article  CAS  PubMed  Google Scholar 

  18. Gartshore G, Patterson J, Macrae IM. Influence of ischemia and reperfusion on the course of brain tissue swelling and blood-brain barrier permeability in a rodent model of transient focal cerebral ischemia. Exp Neurol. 1997;147(2):353–60.

    Article  CAS  PubMed  Google Scholar 

  19. Kondo T, Reaume AG, Huang TT, Carlson E, Murakami K, Chen SF, et al. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J Neurosci. 1997;17(11):4180–9.

    CAS  PubMed  Google Scholar 

  20. Osborne KA, Shigeno T, Balarsky AM, Ford I, McCulloch J, Teasdale GM, et al. Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1987;50(4):402–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Geng X, Elmadhoun O, Peng C, Ji X, Hafeez A, Liu Z, et al. Ethanol and normobaric oxygen: novel approach in modulating pyruvate dehydrogenase complex after severe transient and permanent ischemic stroke. Stroke. 2015;46(2):492–9.

    Article  CAS  PubMed  Google Scholar 

  22. Liang X, Hu Q, Li B, McBride D, Bian H, Spagnoli P, et al. Follistatin-like 1 attenuates apoptosis via disco-interacting protein 2 homolog A/Akt pathway after middle cerebral artery occlusion in rats. Stroke. 2014;45(10):3048–54.

    Article  CAS  PubMed  Google Scholar 

  23. Liu X, Zhao S, Liu F, Kang J, Xiao A, Li F, et al. Remote ischemic postconditioning alleviates cerebral ischemic injury by attenuating endoplasmic reticulum stress-mediated apoptosis. Translat Stroke Res. 2014;5(6):692–700.

    Article  CAS  Google Scholar 

  24. Su J, Zhang T, Wang K, Zhu T, Li X. Autophagy activation contributes to the neuroprotection of remote ischemic perconditioning against focal cerebral ischemia in rats. Neurochem Res. 2014;39(11):2068–77.

    Article  CAS  PubMed  Google Scholar 

  25. Harvey J, Rasmussen T. Occlusion of the middle cerebral artery: an experimental study. Arch Neurol Psychiatry. 1951;66(1):20–9.

    Article  CAS  Google Scholar 

  26. Meyer JS, Denny-Brown D. The cerebral collateral circulation. I. Factors influencing collateral blood flow. Neurology. 1957;7(7):447–58.

    Article  CAS  PubMed  Google Scholar 

  27. Sundt Jr TM, Waltz AG. Experimental cerebral infarction: retro-orbital, extradural approach for occluding the middle cerebral artery. Mayo Clin Proc. 1966;41(3):159–68.

    PubMed  Google Scholar 

  28. Robinson RG, Shoemaker WJ, Schlumpf M, Valk T, Bloom FE. Effect of experimental cerebral infarction in rat brain on catecholamines and behaviour. Nature. 1975;255(5506):332–4.

    Article  CAS  PubMed  Google Scholar 

  29. 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(4):738–43.

    Article  CAS  PubMed  Google Scholar 

  30. Chen ST, Hsu CY, Hogan EL, Juan HY, Banik NL, Balentine JD. Brain calcium content in ischemic infarction. Neurology. 1987;37(7):1227–9.

    Article  CAS  PubMed  Google Scholar 

  31. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab. 1990;10(2):290–3.

    Article  CAS  PubMed  Google Scholar 

  32. Belayev L, Khoutorova L, Deisher TA, Belayev A, Busto R, Zhang Y, et al. Neuroprotective effect of SolCD39, a novel platelet aggregation inhibitor, on transient middle cerebral artery occlusion in rats. Stroke. 2003;34(3):758–63.

    Article  CAS  PubMed  Google Scholar 

  33. Lee J, Lee JK, Han K. InfarctSizer: computing infarct volume from brain images of a stroke animal model. Comput Methods Biomech Biomed Eng. 2011;14(6):497–504.

    Article  Google Scholar 

  34. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30(12):2752–8.

  35. Tureyen K, Vemuganti R, Sailor KA, Dempsey RJ. Infarct volume quantification in mouse focal cerebral ischemia: a comparison of triphenyltetrazolium chloride and cresyl violet staining techniques. J Neurosci Methods. 2004;139(2):203–7.

    Article  CAS  PubMed  Google Scholar 

  36. Boltze J, Nitzsche B, Geiger KD, Schoon H-A. Histopathological investigation of different MCAO modalities and impact of autologous bone marrow mononuclear cell administration in an ovine stroke model. Translat Stroke Res. 2011;2(3):279–93.

    Article  Google Scholar 

  37. Leach MJ, Swan JH, Eisenthal D, Dopson M, Nobbs M. BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Stroke. 1993;24(7):1063–7.

    Article  CAS  PubMed  Google Scholar 

  38. Liu X, Ye M, An C, Pan L, Ji L. The effect of cationic albumin-conjugated PEGylated tanshinone IIA nanoparticles on neuronal signal pathways and neuroprotection in cerebral ischemia. Biomaterials. 2013;34(28):6893–905.

    Article  CAS  PubMed  Google Scholar 

  39. Ostrowski RP, Schulte RW, Nie Y, Ling T, Lee T, Manaenko A, et al. Acute splenic irradiation reduces brain injury in the rat focal ischemic stroke model. Translat Stroke Res. 2012;3(4):473–81.

    Article  CAS  Google Scholar 

  40. Anderson DC, Bottini AG, Jagiella WM, Westphal B, Ford S, Rockswold GL, et al. A pilot study of hyperbaric oxygen in the treatment of human stroke. Stroke. 1991;22(9):1137–42.

    Article  CAS  PubMed  Google Scholar 

  41. England TJ, Gibson CL, Bath PM. Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: a systematic review. Brain Res Rev. 2009;62(1):71–82.

    Article  CAS  PubMed  Google Scholar 

  42. Singhal AB, Benner T, Roccatagliata L, Koroshetz WJ, Schaefer PW, Lo EH, et al. A pilot study of normobaric oxygen therapy in acute ischemic stroke. Stroke. 2005;36(4):797–802.

    Article  PubMed  Google Scholar 

  43. Jin G, Sun PZ, Singhal AB, Ayata C, Lo EH. First-order mathematical modeling of brain swelling in focal cerebral ischemia. Translat Stroke Res. 2010;1(1):65–70.

    Article  Google Scholar 

  44. Mitkari B, Kerkela E, Nystedt J, Korhonen M, Jolkkonen J. Unexpected complication in a rat stroke model: exacerbation of secondary pathology in the thalamus by subacute intraarterial administration of human bone marrow-derived mesenchymal stem cells. J Cereb Blood Flow Metab. 2015;35(3):363–6.

    Article  CAS  PubMed  Google Scholar 

  45. Bhattacharya P, Pandey AK, Paul S, Patnaik R, Yavagal DR. Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against cerebral ischemia/reperfusion injury in rodents. PLoS ONE. 2013;8, e73481.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40(6):2244–50.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Lapchak PA, Zhang JH, Noble-Haeusslein LJ. RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Translat Stroke Res. 2013;4(3):279–85.

    Article  Google Scholar 

  48. Fisher M, Tatlisumak T. Use of animal models has not contributed to development of acute stroke therapies: con. Stroke. 2005;36(10):2324–5.

    Article  PubMed  Google Scholar 

  49. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1(8476):307–10.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by NIH R01 NS043338 grant (J.H.Z.). The authors would like to thank Xiping Liang, Nathanael Matei, and Justin Câmara.

Conflict of Interest

The authors have no conflicts of interest.

Author’s Contributions

Author contributions to the study and manuscript preparation include the following. Conception and design: McBride and Zhang. Acquisition of data: McBride. Analysis and interpretation: all authors. Drafting and critically revising the manuscript: all authors.

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Authors and Affiliations

  1. Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA

    Devin W. McBride, Damon Klebe, Jiping Tang & John H. Zhang

  2. Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA

    John H. Zhang

  3. Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA

    John H. Zhang

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  1. Devin W. McBride
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  2. Damon Klebe
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  4. John H. Zhang
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Correspondence to John H. Zhang.

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McBride, D.W., Klebe, D., Tang, J. et al. Correcting for Brain Swelling’s Effects on Infarct Volume Calculation After Middle Cerebral Artery Occlusion in Rats. Transl. Stroke Res. 6, 323–338 (2015). https://doi.org/10.1007/s12975-015-0400-3

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  • DOI: https://doi.org/10.1007/s12975-015-0400-3

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