Brain serotonergic signaling is coupled to arachidonic acid (AA)-releasing calcium-dependent phospholipase A2. Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders Sensitive Line (FSL) rat model of depression, suggesting that brain AA metabolism may be elevated. To test this hypothesis, 14C-AA was intravenously infused to steady-state levels into control and FSL rats derived from the same Sprague–Dawley background strain, and labeled and unlabeled brain phospholipid and plasma fatty acid concentrations were measured to determine the rate of brain AA incorporation and turnover. Brain AA incorporation and turnover did not differ significantly between controls and FSL rats. Compared to controls, plasma unesterified docosahexaenoic acid was increased, and brain phosphatidylinositol AA and total lipid linoleic acid and n-3 and n-6 docosapentaenoic acid were significantly decreased in FSL rats. Several plasma esterified fatty acids differed significantly from controls. In summary, brain AA metabolism did not change in FSL rats despite reported increased levels of serotonin concentrations, suggesting possible post-synaptic dampening of serotonergic neurotransmission involving AA.

Our objective was to determine whether consumption of a single meal has the potential to alter brain oxylipin content. We examined the cerebrum of mice fed a single high-fat/high-sucrose Western meal or a low-fat/low-sucrose control meal, as well as fasted mice. We found no changes in fatty acid composition of cerebrum across the groups. The cerebral oxylipin profile of mice fed a Western meal is distinct from the profile of mice fed a low-fat/low-sucrose meal. Cerebral gene expression of cyclooxygenase 1, cyclooxygenase 2, and epoxide hydrolase 1 were elevated in Western meal-fed mice compared to low-fat/low-sucrose meal-fed mice. Mice that consumed either meal had lower gene expression of cytochrome P450, family 2, subfamily j, polypeptide 12 than fasted mice. Our data in this hypothesis-generating study indicates that the composition of a single meal has the potential to alter brain oxylipins and the gene expression of the enzymes responsible for their production.

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.