The polyunsaturated omega-3 fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in oily fish. Researchers at the National Institute of Health Research (NIHR) Maudsley Biomedical Research Center studied the effects of high doses of EPA and DHA on neurons grown in the laboratory, and then on patients, to clarify how they reduce inflammation and depression. This novel approach allowed scientists to identify an important molecular mechanism that can aid the development of potential new treatments with omega-3 fatty acids for patients with depression.
The main author Dr. Alessandra Borsini, NIHR Maudsley BRC Senior Postdoctoral Neuroscientist at King’s College London, said, “Through a combination of laboratory and patient research, our study has provided exciting new insights into how omega-3s have anti-inflammatory effects that improve depression For some time we have known that omega-3 PUFAs can produce antidepressant and anti-inflammatory effects, but without further understanding how this happens in the human brain, treatments have been difficult to develop.Our study helped shine a light on it the molecular mechanisms involved in this relationship that may influence the development of potential new treatments for depression using omega-3 PUFA. ”
Previous research has shown that people with major depressive disorder have higher levels of inflammation in their bodies than people without the disorder. There are currently no proven anti-inflammatory treatment strategies for depression, and although two key omega-3 PUFAs, EPA and DHA, have been shown to have anti-inflammatory and antidepressant effects, the exact mechanism is unknown.
Depression in a Dish The study wanted to test the theory that when omega-3 fatty acids are used and processed in the body, some of their metabolites (called lipid mediators) are able to protect the brain from the harmful effects of inflammation. The researchers used a validated human in vitro cell model known as “Depression in a Dish,” developed at the NIHR Maudsley Biomedical Research Center, that uses cells from the hippocampus, a part of the brain that, for many, is cognitive, memory – and areas of fundamental study are important in depression. Hippocampal cells play an important role in the production of new neurons – neurogenesis.
The study showed that treating human hippocampal cells with EPA or DHA before exposure to chemical messengers that are involved in inflammation called cytokines prevented increased cell death and decreased neurogenesis. Both effects had previously been seen in cells exposed only to cytokines. Further research confirmed that these effects were mediated by the formation of several key lipid mediators produced by EPA and DHA, namely hydroxyeicosapentaenoic acid (HEPE), hydroxydocosahexaenoic acid (HDHA), epoxyeicosatetraenoic acid (EpETE), and epoxydocosapentaenoic acid (EpDPA), and these have been demonstrated for the first time in human hippocampal neurons. Further research showed that treatment with an enzyme inhibitor increased the availability of two of these metabolites (EpETE and EpDPA), suggesting a possible avenue for optimizing future treatments.
Professor Anna Nicolaou, Professor of Biological Chemistry in the Faculty of Medicine and Human Sciences at the University of Manchester, who led the team that measured lipid mediators using mass spectrometry, said, “The lipid mediators that our research has identified degrade relatively quickly in the body , that means they may only be available for a relatively short time. By testing the effects of inhibitors of the enzymes involved in the metabolism of omega-3 PUFAs, we have shown that we can determine their duration of action in this is very important for the development of new treatments and means that patients could be given EPA and DHA along with these enzyme inhibitors in higher doses to increase the amount of these important compounds in their blood over time. ”
Omega-3 metabolites in patients
The study looked at 22 major depression patients who received either 3 grams of EPA or 1.4 grams of DHA daily for 12 weeks. The lipid metabolites of EPA and DHA were measured in their blood before and after the omega-3 PUFA treatment along with a score for their depressive symptoms. In both patient groups, EPA or DHA treatment was associated with an increase in their respective metabolites and a significant improvement in depressive symptoms – an average reduction in symptom scores of 64% and 71% in the EPA and DHA groups, respectively. In addition, higher concentrations of the same metabolites identified in the in vitro experiments correlated with lower depressive symptoms.
The EPA and DHA levels used in this study are concentrations that are highly unlikely to be achieved with ingestion of oily fish, a rich source of omega-3 PUFAs, but require therapeutic supplements.
The results of the study suggest that the bioactive lipid mediators produced by the breakdown of EPA and DHA in the body could be used as a mechanism to reduce depression and inflammation, but ensuring that their effects are prolonged in order to do so this approach is possible to be successful. Previous research suggests that a key enzyme in omega-3 fatty acid metabolism could be a valid drug reuse option and could be used for other inflammation-related brain diseases, including depression, where at least a subset of patients often have chronic levels of Inflammation.
Professor Carmine Pariante, senior author of the article, NIHR Maudsley BRC Affective Disorders Interface with Medicine Theme Lead, said, “Interest in the links between the immune system, inflammation and depression is growing, but we have to develop new treatments in this area better understand the mechanisms behind these relationships. Our study provided important insights into how well-known anti-inflammatory compounds – the omega-3 PUFAs – help reduce depression. By identifying and measuring the exact lipid mediators involved and identifying the enzyme that prolongs their action and having found the same lipid mediators in depressed patients treated with omega-3 PUFA and showing improvements in symptoms, we have provided important information to design clinical studies for future therapeutic approaches with omega-3 fatty acids.
“It is important to emphasize that our research has not shown that simply increasing the omega-3s in our diet or taking supplements can reduce inflammation or depression. The mechanisms behind the association between depression and omega-3 PUFAs are complex and require further research and clinical trials to fully understand how they work and inform future therapeutic approaches. “
The study was a collaboration between researchers from King’s College London, the University of Manchester and China Medical University.
The article Omega-3 Polyunsaturated Fatty Acids Protect Against Inflammation by Production of LOX and CYP450 Lipid Mediators: Relevance to Severe Depression and Human Hippocampal Neurogenesis was published today (Wednesday, June 16) in Molecular Psychiatry.
Notes for editors
For more information and a strictly embargoed copy of the paper by 01:00 a.m. on Wednesday, June 16, 2021, please contact: Franca Davenport, Communications and Engagement Manager, NIHR Maudsley Biomedical Research Center, franca.davenport@kcl. ac.uk or Serena Rianjongdee, Communications and Engagement Officer, NIHR Maudsley Biomedical Research Center, email@example.com
The paper will be available after the lifting of the embargo at: https://www.nature.com/articles/s41380-021-01160-8
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