The role of omega-3 fatty acids in preventing glucocorticoid-induced reduction in human hippocampal neurogenesis and increase in apoptosis

Abstract

Glucocorticoids have been suggested to be involved in several neuropsychiatric disorders, including depression. One of the possible mechanisms through which glucocorticoids contribute to the development of the depressive symptomatology is via regulation of distinct neurogenic mechanisms in the brain. A preventive or protective approach for these patients might be the use of omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are known for they neuroprotective properties. We used the human hippocampal progenitor cell line HPC0A07/03C and pre-treated cells with either EPA or DHA, followed by treatment with the glucocorticoid cortisol either alone, or in co-treatment with the same n-3 PUFA during subsequent 3 days of proliferation and 7 days of differentiation. During proliferation, both EPA and DHA were able to prevent cortisolinduced reduction in proliferation and increase in apoptosis, when used in pre-treatment, and both pre-and cotreatment. During differentiation, EPA was able to prevent cortisol-induced reduction in neurogenesis and increase in apoptosis, when used in pre-treatment, and both pre-and co-treatment only during the proliferation stage; however, DHA required continuous treatment also during the differentiation stage to prevent cortisol-induced reduction in neurogenesis. Using transcriptomic analyses, we showed that both EPA and DHA regulated pathways involved in oxidative stress and immune response [e.g., nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Signal transducer and activator of transcription 3 (STAT3), Interferon (IFN) and Interleukin (IL)-1 signaling], whereas DHA also regulated pathways involved in cell development and neuronal formation [e.g., cAMP-response element binding protein (CREB) signaling]. We provide the first evidence for treatment with both EPA and DHA to prevent cortisol-induced reduction in human hippocampal neurogenesis, and identify novel molecular mechanisms underlying these effects.

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

“…Cell were pre-treated with EPA or DHA (both 10 µM) for 2 days during differentiation, followed by treatment with either IL1β (10,000 pg/ml), IL6 (50 pg/ml) or IFN-α (50,000 pg/ml) for additional 2 days (Fig. 1b ), as in our previous studies with PUFAs and with IL1β [ 13 , 41 ]. Not only we were able to independently replicate the previously described ability of either EPA and DHA to prevent the IL1β-induced reduction in DCX+ cells (Fig.…”

“…We also acknowledge the relatively small sample size of depressed patients used to measure ω-3 PUFAs-derived lipid mediators and the fact that the study was not a randomised placebo control trial; in future studies, it would be important to replicate these findings in a much larger cohort of depressed patients, and to extend our investigations also to other classes of ω-3 PUFAs metabolites, including endocannabinoids [ 58 ]. Finally, it is important to highlight the fact that, concentrations of EPA and DHA (both 10 µM), used in this study and in our previous in vitro studies [ 13 , 37 , 41 ], are concentrations that likely cannot be achieved with consumption of food rich in ω-3 PUFAs [ 59 ], but rather require therapeutic PUFAs supplements. Indeed, these in vitro concentrations resemble those found in the brain of individuals receiving therapeutic doses of ω-3 similar to those administered in our clinical study [ 60 ].…”

Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice

“…Through this, it was expected that IS would directly act on the neuronal cells in uremia. EPA and DHA prevented cortisol-induced hippocampal injury by reducing oxidative damage [21]. Additionally, DHA protected hippocampal cells from oxidative damage [22].…”

Preserving Brain LPC‐DHA by Plasma Supplementation Attenuates Brain Injury after Cardiac Arrest

“…One well‐known function of plasma LPC‐DHA is to transport DHA to the brain and maintain proper DHA content of membrane phospholipids 10 . DHA is an essential omega‐3 fatty acid and its role as an anti‐inflammatory and anti‐apoptotic agent as well as its involvement in mitochondrial membrane structure have been reported 11–13 . Consistently, the deficiency of DHA has been shown to be associated with various neurological diseases, including schizophrenia, 14 Alzheimer's disease, 15 and depression 16 .…”