Isoflurane attenuates blood-brain barrier disruption in ipsilateral hemisphere after subarachnoid hemorrhage in mice

Abstract

Background and purpose: We examined effects of isoflurane, volatile anesthetics, on blood-brain barrier disruption in the endovascular perforation model of subarachnoid hemorrhage (SAH) in mice.

Methods: Animals were assigned to sham-operated, SAH+vehicle-air, SAH+1%, or 2% isoflurane groups. Neurobehavioral function, brain water content, Evans blue dye extravasation, and Western blotting for sphingosine kinases, occludin, claudin-5, junctional adhesion molecule, and vascular endothelial cadherin were evaluated at 24 hours post-SAH. Effects of sphingosine kinase (N,N-dimethylsphingosine) or sphingosine-1-phosphate receptor-1/3 (S1P1/3) inhibitors (VPC23019) on isoflurane's action were also examined.

Results: SAH aggravated neurological scores, brain edema, and blood-brain barrier permeability, which were prevented by 2% but not 1% isoflurane posttreatment. Two percent isoflurane increased sphingosine kinase-1 expression and prevented a post-SAH decrease in expressions of the blood-brain barrier-related proteins. Both N,N-dimethylsphingosine and VPC23019 abolished the beneficial effects of isoflurane.

Conclusions: Two percent isoflurane can suppress post-SAH blood-brain barrier disruption, which may be mediated by sphingosine kinase 1 expression and sphingosine-1-phosphate receptor-1/3 activation.

Figure 1

SAH grade (A), neurological score (B), brain water content (C) and Evans blue dye extravasation (D) at 24 hours post-SAH (study 1). Vehicle-air, SAH+vehicle-air group; 1% or 2% ISO, SAH+1% or 2% isoflurane group; left or right, left or right cerebral hemisphere; values, median±25th to 75th percentiles (A, B) or mean±SD (C, D); *P<0.05, Kruskal-Wallis test (A, B) or ANOVA (C, D).

Figure 2

Representative Western blots and quantitative analysis of occludin (A), JAM-A (B), claudin-5 (C) and VE-cadherin (D) expressions in the left cerebral hemisphere at 24 hours post-SAH (study 1). The protein band density values are calculated as a ratio of that of β-actin. Vehicle-air, SAH+vehicle-air group; 2% isoflurane, SAH+2% isoflurane group; values, mean±SD; *P<0.05, ANOVA.

Figure 3

Brain water content (A), representative Western blots and quantitative analysis of SphK1 (B), claudin-5 (C) and VE-cadherin (D) expressions in the left cerebral hemisphere at 24 hours post-SAH (study 2). The protein band density values are calculated as a ratio of that of β-actin. Left or right, left or right cerebral hemisphere; values, mean±SD; *P<0.05, ANOVA.