A key molecular mechanism underpinning the anti-inflammatory, antidepressant, and neuroprotective effects of omega-3 fatty acids has been identified. In findings that could lead to the development of new treatments for depression, the research provides the “first evidence” that hippocampal neurons are able to produce two key lipid metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) – lipoxygenase and cytochrome P450, lead investigator Alessandra Borsini, PhD, told this news organization.
This is how EPA and DHA exert their anti-inflammatory and neurogenic properties in vitro, as well as antidepressant properties in patients with depression, said Dr. Borsini, from King’s College London.
“Indeed, we found evidence for a correlation between increased levels of these metabolites and a decrease in severity of depressive symptoms in patients with major depressive disorder,” Dr. Borsini said.
The study was published online June 16 in Molecular Psychiatry.
‘Depression in a dish’
Despite the known role of inflammation in depression, there remains a lack of data showing anti-inflammatory strategies that are effective, safe for everyday use, and with a clear mechanism of action, the researchers note.
Dr. Borsini and colleagues tested the theory that when EPA and DHA are metabolized, some of their metabolites, or lipid mediators, can protect the brain from the harmful effects of inflammation. They used a validated “depression in a dish” in vitro human hippocampal cell model to test their theory.
They found that treating human hippocampal cells with EPA or DHA before exposing them to cytokines prevented increased cell death and decreased neurogenesis. Both these impacts had been previously observed in cells exposed to cytokines alone.
They confirmed that these effects were mediated by the formation of several key lipid mediators produced by EPA and DHA – namely hydroxyeicosapentaenoic acid, hydroxydocosahexaenoic acid, epoxyeicosatetraenoic acid (EpETE), and epoxydocosapentaenoic acid (EpDPA).
It’s the first time these lipid mediators were detected in human hippocampal neurons, the researchers say.
They also found that treating the neurons with an enzyme inhibitor increased the availability of two of these metabolites (EpETE and EpDPA), suggesting a possible way by which future treatments could be optimized.
The findings were replicated in 22 patients with major depression given either EPA (3 g/day) or DHA (1.4 g/day) for 12 weeks. In both groups, EPA or DHA treatment was associated with an increase in their respective metabolites and significant improvement in depressive symptoms.
The average reduction in symptom scores was 64% and 71% in the EPA and DHA groups, respectively, and there was some evidence that higher levels of the same metabolites correlated with less severe depressive symptoms.
“For some time we have known that omega-3 [polyunsaturated fatty acid (PUFA)] can induce antidepressant and anti-inflammatory effects, but, without further understanding of how this happens in the human brain, it has been difficult to develop treatments,” Dr. Borsini said in a news release.
“ which can inform the development of potential new treatments for depression using omega-3 PUFA,” Dr. Borsini added.
“We need to be cautious when interpreting data generated from the correlation between levels of metabolites and depressive symptoms as findings require further validation in a bigger sample of patients,” Dr. Borsini said.
“It is important to highlight that our research has not shown that by simply increasing omega-3 fatty acids in our diets or through taking nutritional supplements we can reduce inflammation or depression,” study author Carmine Pariante, MD, PhD, from King’s College London, said in the news release.
“The mechanisms behind the associations between depression and omega-3 PUFA are complicated and require further research and clinical trials to fully understand how they work and inform future therapeutic approaches,” Dr. Pariante said.