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

Neurosci Biobehav Rev. 2018 Apr:87:56-66. doi: 10.1016/j.neubiorev.2018.01.010. Epub 2018 Feb 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use
  • Comorbidity
  • Epoxide Hydrolases / antagonists & inhibitors
  • Epoxide Hydrolases / metabolism*
  • Humans
  • Inflammation / complications
  • Inflammation / metabolism*
  • Inflammation / prevention & control
  • Mental Disorders / complications
  • Mental Disorders / metabolism*
  • Mental Disorders / prevention & control
  • Oxidative Stress
  • Vascular Diseases / complications
  • Vascular Diseases / metabolism*
  • Vascular Diseases / prevention & control

Substances

  • Anti-Inflammatory Agents
  • Epoxide Hydrolases