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 cortisol-induced reduction in proliferation and increase in apoptosis, when used in pre-treatment, and both pre- and co-treatment. 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.
Highlights
Glucocorticoids have been suggested to be involved in neurological disorders associated with stress, includingBorsini et al Translational Psychiatry (2020)10:219 inhibit early hippocampal progenitor cells differentiation into neurons[7,8,9,10,11]
Pre-treatment with eicosapentaenoic acid (EPA) followed by cortisol either alone (EC) or in co-treatment with EPA (EEC) prevented the reduction in BrdU+ cells originally caused by cortisol (-C)
Pre-treatment with EPA followed by cortisol either alone (EC) or in co-treatment with EPA (EEC) prevented the increase in Caspase 3+ cells originally caused by cortisol (-C)
Summary
Glucocorticoids have been suggested to be involved in neurological disorders associated with stress, includingBorsini et al Translational Psychiatry (2020)10:219 inhibit early hippocampal progenitor cells differentiation into neurons[7,8,9,10,11]. Alteration in the stress response and in glucocorticoid production have often been associated with the depressive psychopathology, there are still no effective therapeutic approaches for these sub-group of patients. The exact mechanisms underlying their mode of action remain unknown, n-3 PUFAs are important in regulating immune and oxidative stress responses in the brain, by inhibiting activation of pro-inflammatory cytokines and inducing the production of antioxidant molecules[19]. In turns, this would contribute to a sustained cell proliferation and neurogenesis[20]
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