Bilateral carotid artery stenosis (BCAS) is one experimental model of vascular dementia that is thought to preferentially impact brain white matter. Indeed, it is generally accepted that hippocampal and cortical pathology is not observed prior to 30 days post-injury. Since changes in the blood-brain barrier (BBB) permeability are known to precede more overt brain pathology in a variety of diseases, we hypothesized that BBB changes could occur earlier after BCAS in the hippocampus, striatum and cortex and be a precursor of longer term pathology in these regions. In our study, 3 month old male C57/Bl6 mice underwent BCAS with 0.18 mm coils or sham surgery control and changes in BBB were analyzed by collagen IV (vascular basement membrane component), claudin-5 and occludin (tight junction proteins), Evan’s blue (permeability marker), and Ki-67 (marker of cell proliferation) immunohistochemistry, protein and RNA expression levels after 3, 7, 14, or 21 days. Surprisingly, significant changes in markers of cerebrovascular integrity were detected within 7 days compared to sham animals, not only in the striatum but also in the hippocampus. Increased astrocyte and microglia activation was also observed in these regions and TUNEL staining also indicates cell death in the hippocampus within 7 days. While few changes were observed in the cortex, some of the animals did experience cortical ischemic infarcts within 14 days. In conclusion, this study demonstrates for the first time that changes in the BBB occur shortly after BCAS in multiple regions throughout the brain and suggests that such changes might underlie the gradual development of BCAS non-white matter pathology.
Verapamil-induced breakdown of the blood–brain barrier presenting as a transient right middle cerebral artery syndrome
