Late changes in blood–brain barrier permeability in a rat tMCAO model of stroke detected by gadolinium-enhanced MRI

ABSTRACT

Objectives

After cerebral ischaemia the blood–brain barrier (BBB) may be compromised and this has been observed in both clinical and preclinical studies. The timing of BBB disruption after ischaemia has long been considered to be biphasic, however some groups contest this view. Therefore, the purpose of this study was to characterize the BBB permeability timecourse in a rat model at both acute and chronic time points

Methods

Unilateral transient middle cerebral artery occlusion (tMCAO) was performed in 15 male Sprague Dawley rats. Change in T1-weighted MR signal before and after an injection of gadolinium-based contrast agent was calculated voxelwise to derive a BBB permeability index (BBBPI) at both early (6 h, 12 h, and 24 h) and late (7 and 14 days) time points.

Results

As expected, BBBPI in the non-lesioned ROI was not significantly different from pre-occlusion baseline at any time point. However, BBBPI in the ipsilateral (lesioned) ROI was statistically different to baseline at day 7 (p < 0.001) and day 14 (p < 0.01) post-tMCAO. There was a small, but not-significant increase in BBBPI in the earlier phase (at 6 hours).

Discussion

Our results indicate a significant late opening of the BBB. This is important as the majority of previous studies have only characterised an early acute BBB permeability in ischemia. However, the later period of increased permeability may indicate an optimal time for drug delivery across the BBB, when it is especially suited to drugs targeting delayed processes.

KEYWORDS:

• Stroke
• transient middle cerebral artery occlusion
• blood-brain barrier
• chronic
• MRI
• contrast-enhanced

Acknowledgments

The authors are grateful to Dr Aisling Dixon for her helpful editing of the manuscript.

Disclosure statement

Author E. Irving, was employed by GlaxoSmithKline. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Funding

The work was supported by GlaxoSmithKline to SCR Williams and departmental funds (Institute of Psychiatry, Psychology and Neuroscience, King’s College London)