PMID- 34131267 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20231105 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 26 IP - 11 DP - 2021 Nov TI - 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. PG - 6773-6788 LID - 10.1038/s41380-021-01160-8 [doi] AB - 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 (IL1beta), IL6 and interferon-alpha (IFN-alpha). 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. CI - (c) 2021. The Author(s). FAU - Borsini, Alessandra AU - Borsini A AUID- ORCID: 0000-0003-4410-7865 AD - Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK. alessandra.borsini@kcl.ac.uk. FAU - Nicolaou, Anna AU - Nicolaou A AD - Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. AD - Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. FAU - Camacho-Munoz, Dolores AU - Camacho-Munoz D AD - Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. FAU - Kendall, Alexandra C AU - Kendall AC AD - Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. FAU - Di Benedetto, Maria Grazia AU - Di Benedetto MG AD - Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK. AD - Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy. FAU - Giacobbe, Juliette AU - Giacobbe J AD - Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK. FAU - Su, Kuan-Pin AU - Su KP AD - Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK. cobolsu@gmail.com. AD - College of Medicine, China Medical University, Taichung, Taiwan. cobolsu@gmail.com. AD - Depression Center, An-Nan Hospital, China Medical University, Tainan, Taiwan. cobolsu@gmail.com. FAU - Pariante, Carmine M AU - Pariante CM AUID- ORCID: 0000-0002-9132-5091 AD - Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK. LA - eng GR - WT094028/WT_/Wellcome Trust/United Kingdom GR - DH_/Department of Health/United Kingdom GR - MR/J002739/1/MRC_/Medical Research Council/United Kingdom GR - MR/N029488/1/MRC_/Medical Research Council/United Kingdom GR - MR/L014815/1/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - G108/603/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210616 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Fatty Acids, Omega-3) RN - 25167-62-8 (Docosahexaenoic Acids) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - AAN7QOV9EA (Eicosapentaenoic Acid) RN - EC 1.13.11.12 (Lipoxygenase) SB - IM MH - Cytochrome P-450 Enzyme System/metabolism/pharmacology/therapeutic use MH - Depression MH - *Depressive Disorder, Major/drug therapy MH - Docosahexaenoic Acids/pharmacology MH - Eicosapentaenoic Acid/pharmacology/therapeutic use MH - *Fatty Acids, Omega-3/metabolism/pharmacology MH - Hippocampus/metabolism MH - Humans MH - Inflammation/metabolism MH - Lipoxygenase/metabolism/pharmacology/therapeutic use MH - Neurogenesis PMC - PMC8760043 COIS- Alessandra Borsini and Carmine M. Pariante have received research funding from Johnson & Johnson for research on depression and inflammation which included cellular work (2012-2018); moreover, Carmine M. Pariante is funded by a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA) Consortium (104025), which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. The work presented in this paper is unrelated to this funding. EDAT- 2021/06/17 06:00 MHDA- 2022/03/15 06:00 PMCR- 2021/06/16 CRDT- 2021/06/16 06:39 PHST- 2021/02/13 00:00 [received] PHST- 2021/05/05 00:00 [accepted] PHST- 2021/04/29 00:00 [revised] PHST- 2021/06/17 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/06/16 06:39 [entrez] PHST- 2021/06/16 00:00 [pmc-release] AID - 10.1038/s41380-021-01160-8 [pii] AID - 1160 [pii] AID - 10.1038/s41380-021-01160-8 [doi] PST - ppublish SO - Mol Psychiatry. 2021 Nov;26(11):6773-6788. doi: 10.1038/s41380-021-01160-8. Epub 2021 Jun 16.