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A new model of focal cerebral ischemia in the miniature pig

Hideaki Imai Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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 M.D., Ph.D.
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Kenjiro Konno Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Mitsunobu Nakamura Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Tatsuya Shimizu Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Chisato Kubota Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Koji Seki Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Fumiaki Honda Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Shinichiro Tomizawa Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Yukitaka Tanaka Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Hidekazu Hata Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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Nobuhito Saito Department of Neurosurgery, and Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

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 M.D., Ph.D.
Page Range:
123–132
Volume/Issue:
Volume 104: Issue 2
DOI link:
https://doi.org/10.3171/ped.2006.104.2.9
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Object

The purpose of this set of studies is to design a minimally invasive, reproducible stroke model in the gyrencephalic brain. This paper provides information on both surgical technique and methods of quantification of ischemic damage to both gray and white matter in the miniature pig.

Methods

Sixteen male miniature pigs were randomly divided into three groups and underwent transcranial surgery involving a frontotemporal approach with orbital rim osteotomy for permanent middle cerebral artery occlusion (MCAO; five animals), permanent internal carotid artery occlusion (ICAO; six animals), and a sham operation (five animals). Histological mapping and magnetic resonance (MR) imaging were used to delineate the areas of ischemic damage. The volumes of infarction measured directly from MR images were 16.2 ± 1.1, 1.5 ± 0.5, and 0.0 ± 0.0 cm3 (mean ± standard deviation [SD], p < 0.001) in the MCAO, ICAO, and sham-operated groups, respectively. The areas of ischemia identified through histological analysis and MR imaging showed a good correlation (r2 = 0.86, p < 0.0001). Immunohistochemical staining with an amyloid precursor protein (APP) antibody was used to evaluate axonal damage and calculate a total APP score for axonal damage of 44.8 ± 2.9 in the MCAO, 13.2 ± 6.6 in the ICAO, and 0.0 ± 0.0 (mean ± SD, p < 0.002) in the sham-operated animals.

Conclusions

This new model of focal cerebral ischemia induces a reproducible amount of ischemic damage in both gray and white matter, and has significant utility for studies of the pathophysiology of ischemia in the gyrencephalic brain and for assessment of the therapeutic efficacy of drugs prior to the initiation of human clinical trials.

Abbreviations used in this paper:

ANOVA = analysis of variance; APP = amyloid precursor protein; CSF = cerebrospinal fluid; DW = diffusion-weighted; ICA = internal carotid artery; ICAO = ICA occlusion; MABP = mean arterial blood pressure; MCA = middle cerebral artery; MCAO = MCA occlusion; MR = magnetic resonance; PBS = phosphate-buffered saline; SD = standard deviation.
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Contributor Notes

Address reprint requests to: Hideaki Imai, M.D., Ph.D., Department of Neurosurgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. email: hideimai@showa.gunma-u.ac.jp.
  • 1

    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 8:474–485, 1988

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Brozici M, , van der Zwan A, & Hillen B: Anatomy and functionality of leptomeningeal anastomoses: a review. Stroke 34:2750–2762, 2003

  • 3

    Coleman MP, & Perry VH: Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 25:532–537, 2002

  • 4

    Crowell RM, , Marcoux FW, & DeGirolami U: Variability and reversibility of focal cerebral ischemia in unanesthetized monkeys. Neurology 31:1295–1302, 1981

  • 5

    Dare AO, , Landi MK, , Lopes DK, & Grand W: Eyebrow incision for combined orbital osteotomy and supraorbital minicraniotomy: application to aneurysms of the anterior circulation. Technical note. J Neurosurg 95:714–718, 2001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    De Keyser J, , Sulter G, & Luiten PG: Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing?. Trends Neurosci 22:535–540, 1999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Dewar D, , Yam P, & McCulloch J: Drug development for stroke: importance of protecting cerebral white matter. Eur J Pharmacol 375:41–50, 1999

  • 8

    Felix B, , Leger ME, , Albe-Fessard D, , Marcilloux JC, , Rampin O, & Laplace JP: Stereotaxic atlas of the pig brain. Brain Res Bull 49:1–137, 1999

  • 9

    Frahm HD, , Stephan H, & Stephan M: Comparison of brain structure volumes in Insectivora and Primates. I Neocortex J Hirnforsch 23:375–389, 1982

  • 10

    Furuya K, , Kawahara N, , Kawai K, , Toyoda T, , Maeda K, & Kirino T: Proximal occlusion of the middle cerebral artery in C57Black6 mice: relationship of patency of the posterior communicating artery, infarct evolution, and animal survival. J Neurosurg 100:97–105, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Garcia JH, , Mitchem HL, , Briggs L, , Morawetz R, , Hudetz AG, & Hazelrig JB, et al.: Transient focal ischemia in subhuman primates. Neuronal injury as a function of local cerebral blood flow. J Neuropathol Exp Neurol 42:44–60, 1983

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Gerriets T, , Stolz E, , Walberer M, , Muller C, , Kluge A, & Bachmann A, et al.: Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging. Stroke 35:566–571, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Huang J, , Mocco J, , Choudhri TF, , Poisik A, , Popilskis SJ, & Emerson R, et al.: A modified transorbital baboon model of reperfused stroke. Stroke 31:3054–3063, 2000

  • 14

    Hudgins WR, & Garcia JH: The effect of electrocautery, atmospheric exposure, and surgical retraction on the permeability of the blood-brain-barrier. Stroke 1:375–380, 1970

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Imai H, , Masayasu H, , Dewar D, , Graham DI, & Macrae IM: Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia. Stroke 32:2149–2154, 2001

  • 16

    Imai H, , McCulloch J, , Graham DI, , Masayasu H, & Macrae IM: New method for the quantitative assessment of axonal damage in focal cerebral ischemia. J Cereb Blood Flow Metab 22:1080–1089, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Kitagawa K, , Matsumoto M, , Yang G, , Mabuchi T, , Yagita Y, & Hori M, et al.: Cerebral ischemia after bilateral carotid artery occlusion and intraluminal suture occlusion in mice: evaluation of the patency of the posterior communicating artery. J Cereb Blood Flow Metab 18:570–579, 1998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Koizumi J, , Yoshida Y, , Nakazawa T, & Ooneda G: Experimental studies of ischemic brain edema, I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 8:1–8, 1986

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kuroiwa T, & Okeda R: Checkpoints and pitfalls in the experimental neuropathology of circulatory disturbance. Neuropathology 23:79–89, 2003

  • 20

    Macrae IM: New models of focal cerebral ischaemia. Br J Clin Pharmacol 34:302–308, 1992

  • 21

    Macrae IM, , Robinson MJ, , Graham DI, , Reid JL, & McCulloch J: Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences. J Cereb Blood Flow Metab 13:276–284, 1993

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    O'Brien MD, & Waltz AG: Transorbital approach for occluding the middle cerebral artery without craniectomy. Stroke 4:201–206, 1973

  • 23

    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 50:402–410, 1987

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Park CK, , Nehls DG, , Graham DI, , Teasdale GM, & McCulloch J: The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol 24:543–551, 1988

  • 25

    Sakoh M, , Ostergaard L, , Gjedde A, , Rohl L, , Vestergaard-Poulsen P, & Smith DF, et al.: Prediction of tissue survival after middle cerebral artery occlusion based on changes in the apparent diffusion of water. J Neurosurg 95:450–458, 2001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Sharkey J, & Butcher SP: Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 371:336–339, 1994

  • 27

    Stroke Therapy Academic Industry Roundtable (STAIR): Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–2758, 1999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Valeriani V, , Dewar D, & McCulloch J: Quantitative assessment of ischemic pathology in axons, oligodendrocytes, and neurons: attenuation of damage after transient ischemia. J Cereb Blood Flow Metab 20:765–771, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Virley D, , Hadingham SJ, , Roberts JC, , Farnfield B, , Elliott H, & Whelan G, et al.: A new primate model of focal stroke: endothelin-1–induced middle cerebral artery occlusion and reperfusion in the common marmoset. J Cereb Blood Flow Metab 24:24–41, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Yam PS, , Dunn LT, , Graham DI, , Dewar D, & McCulloch J: NMDA receptor blockade fails to alter axonal injury in focal cerebral ischemia. J Cereb Blood Flow Metab 20:772–779, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Yoshimoto T, , Sakamoto T, & Suzuki J: Experimental cerebral infarction. Part 1: Production of thalamic infarction in dogs. Stroke 9:211–214, 1978

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