Inhibition of soluble epoxide hydrolase (sEH) protects hippocampal neurons and reduces cognitive decline in type 2 diabetic mice

Abstract

Diabetes mellitus is a metabolic disorder that can lead to cognitive dysfunction. The hippocampus plays an important role in the cognitive function. Research has identified correlations between hippocampal impairment and diabetes, yet their intermediate remains unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects by suppressing inflammation, apoptosis and oxidative stress. In this study, under diabetic conditions both hippocampal injury and cognitive decline are accompanied by upregulation of sEH. Moreover, the sEH inhibitor trans‐4‐[4‐(3‐adamantan‐1‐y1‐ureido)‐cyclohexyloxy]‐benzoic acid (t‐AUCB) prevents cognitive dysfunction and decreased ROS accumulation and apoptosis in the diabetic hippocampus. t‐AUCB treatment restored neuronal synaptic plasticity by restoring the expression of the postsynaptic proteins Postsynaptic density protein‐95 (PSD95) and N‐methyl‐d‐aspartate receptor subunit 2B (NR2B), the levels of which were positively correlated with Proline‐rich tyrosine kinase 2 (Pyk2) levels under diabetic conditions. Thus, we suggest that hippocampal protection via sEH inhibition might be a potential therapeutic approach to attenuate the progression of cognitive decline in diabetes.

Serum metabolomic biomarkers of perceptual speed in cognitively normal and mildly impaired subjects with fasting state stratification

“…Additionally, cardiometabolic disorders and cognition share circulating biomarkers and risk factors 6 . Our primary hypothesis was that cognitive decline is associated with an abrogation of normal epoxy fatty acid status based on findings that inhibition of soluble epoxide hydrolase, an enzyme previously implicated in the regulation of microvascular tone and inflammation, protects hippocampal neuronal death and reduces cognitive decline in mice 7 , and that genetic deletion of this enzyme slows amyloid beta associated Alzheimer’s disease onset in mice 8 . Further studies have shown that sEH inhibition reduces neuroinflammation 9 and alpha-synuclein aggregation 10 , 11 , pathological feature of multiple neurocognitive disorders 12 .…”

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

“…The clinical role of sEHIs has been reviewed [22]. In clinical trials, sEHIs play a protective role in hypertension [94], and in animal models, they demonstrate neuroprotection in stroke [27,28], cerebral hypoperfusion, and in diabetes type 1 and type 2 [29][30][31][32][33]. Our studies show that sEHIs may also be promising therapeutic targets in the microvascular endothelial dysfunction that accompanies Alzheimer's and vascular dementias.…”

“…A HGD is a risk factor for dementia [14] and is associated with poor cognitive performance [15,16], but whether the effect can be reversed has also been unknown. Given that in murine models of diabetes, soluble epoxide hydrolase inhibitors (sEHI) reduce neuroinflammation and cognitive decline [32][33][34], we also aimed to examine their role in our model.…”

“…Inhibitors of sEH (sEHI) have been shown to be protective in animal models of stroke [27,28]. Inhibition of sEH is of great clinical interest as it has also been shown to reduce neuroinflammation and cognitive impairment in animal models of cerebral hypoperfusion and type 1 and type 2 diabetes mellitus [29][30][31][32][33]. Further, the use of sEHI and genetic knockout of the sEH gene reduces cognitive impairment in animal models of age-related cognitive decline and Alzheimer's disease [26,34,35].…”

Free radical biology in neurological manifestations: mechanisms to therapeutics interventions

“…Neurotoxins such as Aβ, epoxide hydrolase (sEH), dichloroacetic acid, paroxetine, NO, and doxorubicin increase the FR concentration, which is responsible for ROS-induced neuronal cell death and ultimately leads to cognitive impairment and synaptic dysfunction. Administration of neurotoxins disrupts the mitochondrial membrane permeability and alters the calcium homeostasis (Toledo et al 2021;Sheikholeslami et al 2021;Wang et al 2021;Wu et al 2021;Wei et al 2021). To reverse the effects of neurotoxin-induced oxidative stress, the efficacy of antioxidant properties has been tested in both in vivo and in vitro conditions.…”