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 peripheral and brain 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.

Keywords: Dementia; Depression; Diabetes; Drug development; ER stress; Heart disease; Inflammasome; Lipidomics; Metabolism; Mitochondrial dysfunction; NLRP3; Neurodegeneration; Neuroprogression; Obesity; Omega-3 fatty acids; Soluble epoxide hydrolase; Stroke.

Figure 1. Hypothetical relationships between depressive disorders, vascular risk factors and cognitive vulnerability mediated by inflammatory activity and oxidative stress

Anti-inflammatory lipid mediators (e.g. fatty acid epoxides) are metabolized by soluble epoxide hydrolase (sEH) into less beneficial (less bioactive) and sometimes even pro-inflammatory or cytotoxic oxylipin diol species. Increased sEH activity in the brain and vasculature in depressive disorders may confer vulnerability to vascular risk factors that affect neurovascular coupling/cerebral blood flow/brain metabolism and contribute to cognitive and mood symptoms, and predispose cerebrovascular disease that contribute to neuroprogression and cognitive decline.

Figure 2. Enzymatic synthesis of oxylipins from arachidonic acid (AA; 20:4 n-6), eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3)

Polyunsaturated fatty acids, including AA, EPA and DHA, are precursors to oxidized fatty acid metabolites, commonly known as oxylipins. In this figure, fatty acid precursors and their respective metabolites share the same color code. Prostaglandins, thromboxanes and resolvins are produced from AA and EPA though the cyclooxygenase pathway (COX) pathway. The lipoxygenase (LOX) pathway produces hydroperoxy-metabolites, such as hydroperoxyeicosatetraenoic acids (HpETEs), hydroperoxyeicosapentaenoic acids (HpEPEs) and hydroperoxydocosahexaenoic acids (HpDoHEs), that are rapidly converted into hydroxy-metabolites, including hydroxyeicosatetraenoic acids (HETEs), hydroxyeicosapentaenoic acids (HEPEs) or hydroxydocosahexaenoic acids (HDoHEs). Hydroxy-metabolites from the LOX pathway can then be converted into dihydroxy metabolites, such as dihydroxyeicosatetraenoic acids (DiHETEs), dihydroxyeicosapentaenoic acids (DiHEPEs) or dihydroxydocosahexaenoic acids (DiHDoHEs), and into keto-metabolites, such as oxo-eicosatetraenoic acids (oxo-ETEs). Leukotrienes and lipoxins from AA and EPA, as well as maresins, protectins and resolvins from DHA are also synthesized through the LOX pathway. Cytochrome p450 enzymes are oxidative enzymes that generate hydroxy-metabolites on activated or terminal carbons or epoxides at olefinic bonds. Epoxides generated by Cytochromie p450s include epoxyeicosatrienoic acids (EpETrEs), epoxyeicosatetraenoic acids (EpETEs) and epoxydocosapentaenoic acids (EpDPEs). These largely anti-inflammatory epoxy-metabolites can be converted largely by soluble epoxide hydrolase (sEH) into their respective diols, dihydroxyeicosatrienoic acids (DiHETrEs), dihydroxyeicostetraenoic acids (DiHETEs) and dihydroxydocosapentaenoic acids (DiHDPES).

Figure 3

Biotransformation of arachidonic acid and docosahexaenoic acid into epoxides by cytochrome p450s, and subsequent biotransformation to corresponding diols by sEH.