Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis

Abstract

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1β), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

“…In contrast, cluster headaches, which are uncommon in ME/CFS and GWI, may be interpreted as exteroceptive pain with the arousal of sympathetic fight-flight reactions, motor agitation, and restlessness. The molecular mechanisms of sickness behaviors are complex but may involve IL6, IL1-beta, INF-alpha, and other cytokines as well as modulation of arachidonic acid cytochrome P450 metabolites and phosphatidylinositol derivatives by eicosapentaenoic acid (EPA) and effects on cannabinoid CB2 receptors [ 135 , 136 , 137 , 138 ]. EPA may have some benefits for treating anxiety [ 139 ] and PTSD [ 140 , 141 ] but has small non-clinical effects compared to placebo in depression [ 142 ].…”

Soluble Epoxide Hydrolase and Diabetes Complications

“…Perturbations in the CYP450-sEH pathway have now been reported in clinical studies of seasonal depression [ 80 ], major depression without T2DM [ 81 ], and major depression with T2DM [ 82 ]. A recent study found increased plasma levels of 17(18)-EpETE and 19(20)EpDPE in depressed patients receiving EPA or DHA supplementation, where higher epoxide levels were correlated with lower depression severity, suggesting that the benefits of omega-3 supplementation may depend on metabolism into neuroprotective mediators [ 81 ].…”

“…Perturbations in the CYP450-sEH pathway have now been reported in clinical studies of seasonal depression [ 80 ], major depression without T2DM [ 81 ], and major depression with T2DM [ 82 ]. A recent study found increased plasma levels of 17(18)-EpETE and 19(20)EpDPE in depressed patients receiving EPA or DHA supplementation, where higher epoxide levels were correlated with lower depression severity, suggesting that the benefits of omega-3 supplementation may depend on metabolism into neuroprotective mediators [ 81 ]. In human hippocampal cells, co-treatment with EPA and DHA prevented cytokine-induced reduction in neurogenesis and apoptosis via increases in EPA-derived 17(18)-EpETE (17,18-Epoxy-5,8,11,14-eicosatetraenoic acid) and DHA-derived 19(20)EpDPE levels, an effect that was further enhanced with the addition of an sEH inhibitor [ 81 ].…”

“…Given that oxylipins are derived from different parent fatty acids [ 83 ], there remains a need to delineate the roles of specific species to understand overall function of the CYP450-sEH pathway in T2DM complications. This may be relevant if an approach of dietary supplementation of relevant parent fatty acids, with or without sEH inhibition, might be used with the former combination testing for potential synergistic effects [ 7 ], [ 81 ]. The type of fat intake may affect diabetes complications [ 12 ], so trials and observational studies should consider intake of specific parent fatty acids (e.g., EPA, DHA, AA) in examining dietary effects on diabetes complications.…”

sEH-derived metabolites of linoleic acid drive pathologic inflammation while impairing key innate immune cell function in burn injury

“…This factor, combined with agricultural practices driven toward corn production and a dietary preference toward processed foods, shifted fatty acid composition in the modern Western diet from saturated and monounsaturated to increasing concentrations of polyunsaturated fatty acids (PUFAs), specifically omega-6 linoleic acid (LA, 18:2), resulting in a corresponding increase in LA in human adipose composition since the 1950s ( 1 ). The metabolism of PUFAs results in numerous regulatory lipid mediators that influence inflammation and metabolism, and many observational studies have found associations between concentrations of parent PUFAs, their metabolites, and numerous diseases ( 2 , 3 ). For example, higher dietary intake of omega-3 fatty acids found predominantly in cold-water fish is associated with better health outcomes and antiinflammatory properties ( 4 ), while the omega-6 fatty acids and their metabolites are associated with more complex phenotypes.…”