Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Center for Experimental Drugs and Diagnostics and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
Mol Psychiatry. 2021 Sep;26(9):4605-4615. doi: 10.1038/s41380-020-0786-5. Epub 2020 Jun 5.
Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs potential therapeutic properties remain unknown. There are suggestions in the literature that glial hypofunction is associated with depressive symptoms and that antidepressants may normalize glial function. In this study, induced pluripotent stem cells (iPSC)-derived neuronal stem cell lines were generated from individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or stearic acid (SA). During astrocyte differentiation, we found that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and GDNF production were increased in the astrocytes derived from patients subsequent to n-3 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n-3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of some antidepressants by increasing production of neurotrophic factors. The CREB-dependence and cAMP independence of this process suggests a manner in which n-3 PUFA could augment antidepressant effects. These data also suggest a role for astrocytes in both MDD and antidepressant action.
来自流行病学和实验室研究以及随机安慰剂对照试验的证据表明，补充 n-3 多不饱和脂肪酸（PUFAs）可能对治疗重度抑郁症（MDD）有效。 n-3 PUFAs 潜在治疗特性的机制尚不清楚。文献中有一些建议表明神经胶质功能低下与抑郁症状有关，而抗抑郁药可能使神经胶质功能正常化。在这项研究中，从 MDD 个体中生成了诱导多能干细胞（iPSC）衍生的神经元干细胞系。通过 GFAP 验证了从患者衍生的神经元干细胞（iNSCs）分化而来的星形胶质细胞。用二十碳五烯酸（EPA）、二十二碳六烯酸（DHA）或硬脂酸（SA）处理细胞。在星形胶质细胞分化过程中，我们发现 n-3 PUFAs 增加了 GFAP 表达和 GFAP 阳性细胞形成。 n-3 PUFA 治疗后，源自患者的星形胶质细胞中 BDNF 和 GDNF 的产生增加。硬脂酸（SA）处理没有这种作用。 DHA 和 EPA 还增加了 CREB 活性（磷酸化 CREB），但 SA 没有。此外，当用 n-3 PUFAs 处理这些星形胶质细胞时，cAMP 拮抗剂 RP-cAMPs 不会阻断 n-3 PUFA CREB 激活。然而，CREB 特异性抑制剂（666-15）减弱了 n-3 PUFA 诱导的 BDNF 和 GDNF 产生，表明 CREB 依赖性。总之，这些结果表明 n-3 PUFAs 促进星形胶质细胞分化，并通过增加神经营养因子的产生来模拟某些抗抑郁药的作用。该过程对 CREB 的依赖性和 cAMP 的不依赖性表明 n-3 PUFAs 增强抗抑郁作用的方式。这些数据还表明星形胶质细胞在 MDD 和抗抑郁作用中都起作用。
