Anti-inflammatory effects of omega-3 fatty acids could help
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The omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in oily fish. Researchers assessed the effects of high doses of EPA and DHA to help clarify how they reduce inflammation and depression. This novel approach allowed the scientists to identify an important molecular mechanism that can help inform the development of potential new treatments involving omega-3 fatty acids for patients with depression.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory, and neuroprotective properties. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in this anti-inflammatory, neuroprotective and antidepressant effects.

In vitro, they used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1?), IL6, and interferon-alpha (IFN-?). 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 neurons using mass spectrometry lipidomics of the supernatant.

In fact, like EPA/DHA, co-treatment with these metabolites prevented the 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, the 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 a potential therapeutic strategy for patients suffering from depressive symptoms.

Molecular Psychiatry
Source: https://doi.org/10.1038/s41380-021-01160-8
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