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Publication Detail

Title: Soluble epoxide hydrolase inhibition improves cognitive function and parenchymal artery dilation in a hypertensive model of chronic cerebral hypoperfusion.

Authors: Matin, Nusrat; Fisher, Courtney; Lansdell, Theresa A; Hammock, Bruce D; Yang, Jun; Jackson, William F; Dorrance, Anne M

Published In Microcirculation, (2021 01)

Abstract: OBJECTIVE: Parenchymal arterioles (PAs) regulate perfusion of the cerebral microcirculation, and impaired PA endothelium-dependent dilation occurs in dementia models mimicking chronic cerebral hypoperfusion (CCH). Epoxyeicosatrienoic acids (EETs) are vasodilators; their actions are potentiated by soluble epoxide hydrolase (sEH) inhibition. We hypothesized that chronic sEH inhibition with trifluoromethoxyphenyl-3 (1-propionylpiperidin-4-yl) urea (TPPU) would prevent cognitive dysfunction and improve PA dilation in a hypertensive CCH model. METHODS: Bilateral carotid artery stenosis (BCAS) was used to induce CCH in twenty-week-old male stroke-prone spontaneously hypertensive rats (SHSRP) that were treated with vehicle or TPPU for 8 weeks. Cognitive function was assessed by novel object recognition. PA dilation and structure were assessed by pressure myography, and mRNA expression in brain tissue was assessed by qRT-PCR. RESULTS: TPPU did not enhance resting cerebral perfusion, but prevented CCH-induced memory deficits. TPPU improved PA endothelium-dependent dilation but reduced the sensitivity of PAs to a nitric oxide donor. TPPU treatment had no effect on PA structure or biomechanical properties. TPPU treatment increased brain mRNA expression of brain derived neurotrophic factor, doublecortin, tumor necrosis factor-alpha, sEH, and superoxide dismutase 3, CONCLUSIONS: These data suggest that sEH inhibitors may be viable treatments for cognitive impairments associated with hypertension and CCH.

PubMed ID: 32767848 Exiting the NIEHS site

MeSH Terms: Animals; Brain Ischemia*/drug therapy; Brain Ischemia*/enzymology; Cerebrovascular Circulation/drug effects*; Cognition/drug effects*; Dilatation; Enzyme Inhibitors/chemistry; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Hypertension*/drug therapy; Hypertension*/enzymology; Male; Rats; Rats, Inbred SHR

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