Inhibition of Soluble Epoxide Hydrolase Is Protective against the Multiomic Effects of a High Glycemic Diet on Brain Microvascular Inflammation and Cognitive Dysfunction

Abstract

Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain’s microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH.

Alzheimer’s Disease: An Update and Insights Into Pathophysiology

“…Recent approaches in the treatment of AD include exploring the potentials of some natural products with neuroprotective effects ( Kamil et al, 2018 , 2020 ; Prom-In et al, 2020 ; Kamal et al, 2021 ) and metabolites to modulate signaling pathways associated with neurovascular endothelium through multi-omic analyses ( Corral-Jara et al, 2021 ). There have also been reports on cellular signaling-related sex-dependent effects under hyperglycemic and lipid stress ( Nuthikattu et al, 2020 , 2021 ). However, this review focuses on significant signaling pathways associated with the stages of AD, the potential links between vascular dysfunction and AD, as well as recent developments in “omics”-based approaches in AD.…”

High Glycemia and Soluble Epoxide Hydrolase in Females: Differential Multiomics in Murine Brain Microvasculature

“…A HGD increases the levels of blood sugar and is associated with a higher risk of type 2 diabetes [ 30 ], cardiovascular diseases [ 30 , 31 ], and stroke [ 32 ]. We recently demonstrated in male mice that the HGD induces a detrimental transcriptomic response in the microvessels of the hippocampus [ 33 ], the region central to the formation of memory [ 34 ]. Our studies demonstrated changes in the transcriptome consistent with microvascular dysfunction, oxidation, inflammation, and alterations in mitochondrial function.…”

“…A few studies have investigated the effects of the HGD on the brain and cognitive function showing that a HGD can contribute to vascular dysfunction and reduced cognitive function [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. We have shown deleterious effects of the HGD diet on the male brain microvasculature as a consequence of differential gene expression that is associated with hyperpermeability, apoptosis, and neurovascular inflammation [ 33 ]. Yet, only a few studies have addressed the response of the brain of females to a HGD [ 44 , 45 ].…”

“…We previously reported that treatment with a sEHI reversed many of the transcriptomic changes induced by a HGD in the hippocampal microvessels of male mice [ 33 ]. sEH enzyme converts the vasodilatory and neuro-protective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs) which are biologically less active [ 47 , 48 ].…”

Nutrition for Brain Development

“…Nuthikattu and colleagues [ 2 ] showed, using a multi-omic approach, that a high glycemic diet (HGD) leads to differential expression of 608 genes in vivo. HGD affected gene expression of brain microvessels in memory centers by up-regulating the protein-coding and non-coding genes involved in mitochondrial function, oxidation, inflammation, and microvascular functioning.…”