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. 2015 Jul;46(7):1916-22.
doi: 10.1161/STROKEAHA.114.008560. Epub 2015 May 19.

Soluble Epoxide Hydrolase in Hydrocephalus, Cerebral Edema, and Vascular Inflammation After Subarachnoid Hemorrhage

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Free PMC article

Soluble Epoxide Hydrolase in Hydrocephalus, Cerebral Edema, and Vascular Inflammation After Subarachnoid Hemorrhage

Dominic A Siler et al. Stroke. .
Free PMC article

Abstract

Background and purpose: Acute communicating hydrocephalus and cerebral edema are common and serious complications of subarachnoid hemorrhage (SAH), whose causes are poorly understood. Using a mouse model of SAH, we determined whether soluble epoxide hydrolase (sEH) gene deletion protects against SAH-induced hydrocephalus and edema by increasing levels of vasoprotective eicosanoids and suppressing vascular inflammation.

Methods: SAH was induced via endovascular puncture in wild-type and sEH knockout mice. Hydrocephalus and tissue edema were assessed by T2-weighted magnetic resonance imaging. Endothelial activation was assessed in vivo using T2*-weighted magnetic resonance imaging after intravenous administration of iron oxide particles linked to anti-vascular cell adhesion molecule-1 antibody 24 hours after SAH. Behavioral outcome was assessed at 96 hours after SAH with the open field and accelerated rotarod tests.

Results: SAH induced an acute sustained communicating hydrocephalus within 6 hours of endovascular puncture in both wild-type and sEH knockout mice. This was followed by tissue edema, which peaked at 24 hours after SAH and was limited to white matter fiber tracts. sEH knockout mice had reduced edema, less vascular cell adhesion molecule-1 uptake, and improved outcome compared with wild-type mice.

Conclusions: Genetic deletion of sEH reduces vascular inflammation and edema and improves outcome after SAH. sEH inhibition may serve as a novel therapy for SAH.

Keywords: communicating hydrocephalus; edema; subarachnoid hemorrhage; vascular cell adhesion molecule-1.

Figures

Figure 1
Figure 1
SAH causes similar changes to physiology in both WT and sEHKO mice. A.) Representative gross images (left) and T2-weighted MRI (right) of naïve (top) and SAH (bottom) mice 30 minutes after induction. Blood within CSF space causes the T2-weighted signal to change from white to black (arrows). B.) Representative tracing of ICP with view of waveform (inset), LDF and MAP in a WT SAH mouse during SAH. C.) Average changes in ICP, LDF, and MAP in WT(n=5) and sEHKO(n=5) mice after SAH. There were no significant differences between groups.
Figure 2
Figure 2
SAH induces acute communicating hydrocephalus in both WT and sEHKO mice. A.) representative T2-weighted MRI images at baseline (top) and 6h after SAH (bottom). Expansion of the CSF space occurs at all levels including lateral ventricles (lv), third ventricle (3v), cerebral aqueduct (aq), fourth ventricle (4v), cisterna magna (cm) and the subarachnoid space (arrows). Effacement of the central sulcus is also apparent at 6h after SAH (arrowheads). B.) Ventricular volume changes WT (n=10), sEHKO (n=7) SAH animals and sham(n=5). There is no significant difference between WT and sEHKO SAH mice. C.) Total brain volume change in WT (n=10, sEHKO (n=10) SAH animals and sham (n=5). There is no significant difference between WT and sEHKO SAH mice.
Figure 3
Figure 3
sEHKO mice have less edema than WT mice. A.) representative T2-weighted MRI images in sham (top) WT SAH (middle) and sEHKO SAH (bottom) at 24h after SAH. Edema forms in the specifically within the white matter of the corpus callosum and dorsal hippocampal commissures (arrows). Histological sections (right) of the corpus callosum 72h after SAH show vacuolization within the white matter of SAH mice. B.) Periventricular white matter edema formation as a percent of brain volume in WT (n=10), sEHKO (n=7) and sham (n=5) mice. sEHKO mice have less edema at 24h and 72h after SAH (*=p<0.05). C.) Vacuolization determined by changes in mean pixel intensity of the corpus callosum in WT SAH (n=6), sEHKO SAH (n=6) and sham (n=4) mice 72h after SAH. sEHKO mice have less vacuolization than WT mice (*=p<0.05).
Figure 4
Figure 4
sEHKO mice have less VCAM-1 expression than WT mice after SAH. A.) Representative T2* weighted images in SAH mice (IgG control, WT, and sEHKO) and sham operated mice. Deposition of the VCAM-1 MPIO causes hypointensity on MRI. B.) Representative normalized histogram of voxel intensities within a single WT brain 24h after SAH pre-MPIO (blue) and post-MPIO (red) injection (80min). Voxels below the normalized intensity threshold were used to measure the extent of iron particle deposition. C.) Quantification of MPIO deposition as the increase in iron particles detected 80min after injection in IgG control (n=3) WT SAH (n=7) sEHKO SAH (n=9) and Sham (n=4). sEHKO mice have reduced MPIO deposition compared to WT mice (*=p<0.05).
Figure 5
Figure 5
sEHKO mice have improved outcome after SAH. A.) 96h after SAH (WT n=12, sEHKO n=10) or sham (WT n=10, sEHKO n=10), mice were placed in the open field for 10 min. SAH reduces movement on open field for WT mice (*=p<0.05) but not sEHKO mice (ns=no significance) B.) 96h after SAH (WT=12, sEHKO=8) or sham (WT n=10, sEHKO n=10), animals were timed on the accelerated rotarod for three trials per day for three days. The average time to fall over the nine trials was increased in the sEHKO SAH mice compared to the WT SAH mice (*=p< 0.05).

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