Metabolic/inflammatory/vascular comorbidity in psychiatric disorders; soluble epoxide hydrolase (sEH) as a possible new target

Abstract

The common and severe psychiatric disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are associated with inflammation, oxidative stress and changes in lipid metabolism. Those pathways are implicated in the premature development of vascular and metabolic comorbidities, which account for considerable morbidity and mortality, including increased dementia risk. During endoplasmic reticulum stress, the soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory fatty acid epoxides generated by cytochrome p450 enzymes into their corresponding and generally less anti-inflammatory, or even pro-inflammatory, diols, slowing the resolution of inflammation. The sEH enzyme and its oxylipin products are elevated post-mortem in MDD, BD and schizophrenia. Preliminary clinical data suggest that oxylipins increase with symptoms in seasonal MDD and anorexia nervosa, requiring confirmation in larger studies and other cohorts. In rats, a soluble sEH inhibitor mitigated the development of depressive-like behaviors. We discuss sEH inhibitors under development for cardiovascular diseases, post-ischemic brain injury, neuropathic pain and diabetes, suggesting new possibilities to address the mood and cognitive symptoms of psychiatric disorders, and their most common comorbidities.

Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment

“…Oxylipins can be generated non-enzymatically, or enzymatically via cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases. [4] The cytochrome P450-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) epoxides are essential regulators of inflammatory resolution pathways, [5,6] whereas arachidonic acid (AA)-derived epoxide species (epoxyeicosatrienoic acids; EETs) have vasodilatory effects that regulate blood flow. [7,8] The fatty acid epoxides are inactivated by soluble epoxide hydrolase (sEH), which catalyzes their conversion into less active or inactive diol species, some of which can be cytotoxic.…”

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

“…However, these mediators are broken down into their corresponding diols by soluble epoxide hydrolase (sEH), and inhibition of sEH enhances the beneficial effects of EpFAs such as EETs (16)(17)(18). Potent antiinflammatory effects of EETs and key role of sEH have been reported in multiple animal models, including pain, obesity, depression, and Parkinson's disease (19)(20)(21)(22)(23)(24)(25)(26)(27). However, there are no reports showing the role of sEH in the pathogenesis of neurodevelopmental disorders in offspring after MIA.…”

Oxylipid profiles of dairy cattle vary throughout the transition into early mammary gland involution

“…This may suggest that the epoxides are being rapidly converted to their respective diols at d 0, whereas the conversion may be dampened at d +2. Utilizing soluble epoxide hydrolase inhibitors to prolong the availability of the anti-inflammatory epoxides has been proposed as a therapy for pathologies such as inflammatoryrelated pain, atherosclerosis, and metabolic syndrome in humans (Swardfager et al, 2018). However, these inhibitors have not been investigated in dairy cattle, so whether or not they would be a beneficial therapy for modulating inflammatory responses is unknown.…”