Vascular cognitive impairment (VCI) is the second most common cause of dementia. Reduced cerebral blood flow is thought to play a major role in the etiology of VCI. Therefore, chronic cerebral hypoperfusion has been used to model VCI in rodents. The goal of the current study was to determine the histopathological and neuroimaging substrates of neurocognitive impairments in a mouse model of chronic cerebral hypoperfusion induced by unilateral common carotid artery occlusion (UCCAO). Mice were subjected to sham or right UCCAO (VCI) surgeries. Three months later, neurocognitive function was evaluated using the novel object recognition task, Morris water maze, and contextual and cued fear conditioning tests. Next, cerebral perfusion was evaluated with dynamic susceptibility contrast magnetic resonance imaging (MRI) using an ultra-high fieild (11.75 Tesla) animal MRI system. Finally, brain pathology was evaluated using histology and T2 weighted MRI (magnetic resonance imaging). VCI, but not sham, mice had significantly reduced cerebral blood flow in the right vs. left cerebral cortex. VCI mice showed deficits in object recognition. T2 weighted MRI of VCI brains revealed enlargement of lateral ventricles, which corresponded to areas of hippocampal atrophy upon histological analysis. In conclusion, our data demonstrate that the UCCAO model of chronic hypoperfusion induces hippocampal atrophy and ventricular enlargement, resulting in neurocognitive deficits characteristic of VCI.
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.
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