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

Abstract

Background and Purpose Acute communicating hydrocephalus and cerebral edema are common and serious complications of subarachnoid hemorrhage (SAH), whose etiologies are poorly understood. Using a mouse model of SAH, we determined if 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 WT and soluble epoxide hydrolase knockout (sEHKO) mice. Hydrocephalus and tissue edema were assessed by T2-weighted magnetic resonance imaging (MRI). Endothelial activation was assessed in vivo using T2*-weighted MRI after intravenous administration of iron oxide particles linked to anti-vascular cell adhesion molecule-1 (VCAM-1) antibody 24h after SAH. Behavioral outcome was assessed at 96h after SAH with the open field and accelerated rotarod tests. Results SAH induced an acute sustained communicating hydrocephalus within 6h of endovascular puncture in both WT and sEHKO mice. This was followed by tissue edema, which peaked at 24h after SAH and was limited to white matter fiber tracts. sEHKO mice had reduced edema, less VCAM-1 uptake and improved outcome compared to WT 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.

CYP450-derived oxylipins mediate inflammatory resolution

“…There has been great recent interest in the therapeutic potential of sEH inhibitors as novel antiinflammatories. sEH inhibitors or genetic disruption of sEH in mice reduces inflammation in models of endotoxin-induced pulmonary inflammation (22), ischemia-reperfusion injury (33,34), subarachnoid hemorrhage (35), and the murine ovalbumin model of asthma (36), and in more chronic models including atherogenic diet-induced fatty liver disease and adipose tissue (37) and atherosclerosis (38,39). In contrast, the expression and roles of epoxy-oxylipins during inflammatory resolution have not been investigated.…”

Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage

“…Of note, in aSAH, inflammation appears to represent a source of edema independent of ischemic injury: soluble epoxide hydrolase knock-out mice, which mount a defective vascular inflammatory response following experimental aSAH due to inhibition of NF-κB translocation, demonstrate a reduction in white matter edema despite experiencing an equivalent period of brain hypoperfusion as wild type mice. 40 Multiple lines of evidence suggest that blunting of the inflammatory response represents a valid therapeutic strategy in aSAH. Modulation of microglial activation from a pro- to an anti-inflammatory phenotype via mTOR inhibition prevents edema formation in a rat aSAH model.…”

Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll‐like receptor 4 signaling pathway

“…It is well known that inflammation plays an important role in the pathophysiology of hemorrhagic stroke (47)(48)(49). A growing body of evidence has shown that EBI after SAH is closely associated with a robust inflammatory response in the cerebral cortex (2,4,50). Early increases in inflammatory cytokine production in cerebrospinal fluid and serum independently predict poor outcome in patients with SAH (50,51).…”