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.

糖皮质激素被认为与多种神经精神疾病有关，包括抑郁症。糖皮质激素促进抑郁症状发展的可能机制之一是通过调节大脑中不同的神经源性机制。对这些患者的预防或保护方法可能是使用 omega-3 多不饱和脂肪酸 (n-3 PUFA)、二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA)，这些物质因其神经保护特性而闻名。我们使用人类海马祖细胞系 HPC0A07/03C 和用 EPA 或 DHA 预处理的细胞，然后单独用糖皮质激素皮质醇处理，或在随后的 3 天增殖期间与相同的 n-3 PUFA 共同处理和7天的分化。在增殖过程中，当用于预处理以及预处理和联合处理时，EPA 和 DHA 都能够防止皮质醇诱导的增殖减少和细胞凋亡增加。在分化过程中，当用于预处理时，以及仅在增殖阶段进行预处理和联合处理时，EPA能够防止皮质醇诱导的神经发生减少和细胞凋亡增加；然而，DHA 在分化阶段也需要持续治疗，以防止皮质醇引起的神经发生减少。通过转录组分析，我们发现 EPA 和 DHA 均调节参与氧化应激和免疫反应的途径 [例如，核因子（红细胞衍生 2）样 2 (Nrf2)、信号转导器和转录激活剂 3 (STAT3)、干扰素(IFN) 和白细胞介素 (IL)-1 信号传导]，而 DHA 还调节参与细胞发育和神经元形成的途径 [例如，cAMP-反应元件结合蛋白（CREB）信号传导]。我们提供了第一个证据，表明使用 EPA 和 DHA 进行治疗可预防皮质醇引起的人类海马神经发生减少，并确定了这些作用背后的新分子机制。