A novel model of cerebral hyperperfusion with blood-brain barrier breakdown, white matter injury, and cognitive dysfunction

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  • 1 Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan;
  • 2 Department of Neurosurgery, Menoufia University Graduate School of Medicine, Menoufia, Egypt;
  • 3 Department of Neurosurgical Engineering and Translational Neuroscience, Tohoku University Graduate School of Medicine, Sendai;
  • 4 Department of Neurosurgical Engineering and Translational Neuroscience, Graduate School of Biomedical Engineering, Tohoku University, Sendai; and
  • 5 Department of Neurosurgery, Kohnan Hospital, Sendai, Japan
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OBJECTIVE

Cerebral hyperperfusion (CHP) is associated with considerable morbidity. Its pathophysiology involves disruption of the blood-brain barrier (BBB) with subsequent events such as vasogenic brain edema and ischemic and/or hemorrhagic complications. Researchers are trying to mimic the condition of CHP; however, a proper animal model is still lacking. In this paper the authors report a novel surgically induced CHP model that mimics the reported pathophysiology of clinical CHP including BBB breakdown, white matter (WM) injury, inflammation, and cognitive impairment.

METHODS

Male Sprague-Dawley rats were subjected to unilateral common carotid artery (CCA) occlusion and contralateral CCA stenosis. Three days after the initial surgery, the stenosis of CCA was released to induce CHP. Cortical regional cerebral blood flow was measured using laser speckle flowmetry. BBB breakdown was assessed by Evans blue dye extravasation and matrix metalloproteinase–9 levels. WM injury was investigated with Luxol fast blue staining. Cognitive function was assessed using the Barnes circular maze. Other changes pertaining to inflammation were also assessed. Sham-operated animals were prepared and used as controls.

RESULTS

Cerebral blood flow was significantly raised in the cerebral cortex after CHP induction. CHP induced BBB breakdown evident by Evans blue dye extravasation, and matrix metalloproteinase–9 was identified as a possible culprit. WM degeneration was evident in the corpus callosum and corpus striatum. Immunohistochemistry revealed macrophage activation and glial cell upregulation as an inflammatory response to CHP in the striatum and cerebral cortex. CHP also caused significant impairments in spatial learning and memory compared with the sham-operated animals.

CONCLUSIONS

The authors report a novel CHP model in rats that represents the pathophysiology of CHP observed in various clinical scenarios. This model was produced without the use of pharmacological agents; therefore, it is ideal to study the pathology of CHP as well as to perform preclinical drug trials.

ABBREVIATIONS BBB = blood-brain barrier; BCM = Barnes circular maze; CBF = cerebral blood flow; CCA = common carotid artery; CEA = carotid endarterectomy; CHP = cerebral hyperperfusion; GFAP = glial fibrillary acidic protein; LFB = Luxol fast blue; LSF = laser speckle flowmetry; MAP = mean arterial pressure; mCCAO = modified CCA occlusion; MMP-9 = matrix metalloproteinase–9; OD = optical density; rCBF = regional CBF; ROI = region of interest; WM = white matter.

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Contributor Notes

Correspondence Kuniyasu Niizuma: Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan. niizuma@nsg.med.tohoku.ac.jp.

INCLUDE WHEN CITING Published online October 18, 2019; DOI: 10.3171/2019.7.JNS19212.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

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