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Soluble epoxide hydrolase inhibition reverses cognitive dysfunction in a mouse model of metabolic syndrome by
Thierno M Bah1, Catherine M Davis1, Elyse M Allen1
1Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA.
Abstract:
Midlife metabolic syndrome (MetS) is associated with cognitive impairment in late life. The mechanism of delayed MetS-related cognitive dysfunction (MetSCD) is not clear, but it has been linked to systemic inflammation and chronic cerebral microangiopathy. Currently there is no treatment for late life MetSCD other than early risk factor modification. We investigated the effect of soluble epoxide hydrolase (sEH) inhibitor 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (t-AUCB) on cognitive performance, cerebral blood flow (CBF), and central and peripheral inflammation in the high-fat diet (HFD) model of MetS in mice. At 6 weeks of age, male mice were randomly assigned to receive either HFD or standard chow (STD) for 6 months. Mice received either t-AUCB or vehicle for 4 weeks. Cognitive performance was evaluated, followed by CBF measurement using magnetic resonance imaging (MRI). At the end of the study, blood was collected for measurement of eicosanoids and inflammatory cytokines. The brains were then analyzed by immunohistochemistry for glial activation markers. The HFD caused a significant impairment in novel object recognition. Treatment with t-AUCB increased plasma levels of 14,15-EET, prevented this cognitive impairment and modified hippocampal glial activation and plasma cytokine levels, without affecting CBF in mice on HFD. In conclusion, sEH inhibition for four weeks prevents cognitive deficits in mice on chronic HFD by modulating inflammatory processes without affecting CBF.
Insights
Soluble epoxide hydrolase (sEH) inhibition with t-AUCB prevented cognitive decline in mice fed a high-fat diet. This treatment modulated inflammation without impacting cerebral blood flow, offering a potential therapeutic strategy for metabolic syndrome-related cognitive dysfunction.
Area of Science:
- Neuroscience
- Pharmacology
- Metabolic Disorders
Background:
- Midlife metabolic syndrome (MetS) is linked to late-life cognitive impairment.
- Mechanisms involve systemic inflammation and cerebral microangiopathy.
- No current treatments exist beyond early risk factor modification.
Purpose of the Study:
- To investigate the effects of the sEH inhibitor t-AUCB on cognitive function, cerebral blood flow (CBF), and inflammation in a mouse model of MetS.
- To explore the therapeutic potential of sEH inhibition for MetS-related cognitive dysfunction (MetSCD).
Main Methods:
- Mice were fed a high-fat diet (HFD) or standard chow for 6 months.
- Mice received t-AUCB or vehicle for 4 weeks.
- Cognitive performance, CBF (MRI), plasma eicosanoids/cytokines, and brain glial activation were assessed.
Main Results:
- HFD impaired novel object recognition.
- t-AUCB treatment prevented cognitive impairment in HFD mice.
- t-AUCB increased 14,15-EET, modulated glial activation and cytokines, but did not affect CBF.
Conclusions:
- Four weeks of sEH inhibition with t-AUCB prevents HFD-induced cognitive deficits in mice.
- The protective effect is mediated by modulating inflammatory processes.
- CBF was not affected, suggesting inflammation is a key target for MetSCD treatment.
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