Hisaoka-Nakashima Kazue, Kajitani Naoto, Kaneko Masahiro, Shigetou Takahiro, Kasai Miho, Matsumoto Chie, Yokoe Toshiki, Azuma Honami, Takebayashi Minoru, Morioka Norimitsu, Nakata Yoshihiro
Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan; Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama, Kure, Japan.
Brain Res. 2016 Mar 1;1634:57-67. doi: 10.1016/j.brainres.2015.12.057. Epub 2016 Jan 4.
A significant role of brain-derived neurotrophic factor (BDNF) has been previously implicated in the therapeutic effect of antidepressants. To ascertain the contribution of specific cell types in the brain that produce BDNF following antidepressant treatment, the effects of the tricyclic antidepressant amitriptyline on rat primary neuronal, astrocytic and microglial cortical cultures were examined. Amitriptyline increased the expression of BDNF mRNA in astrocytic and microglial cultures but not neuronal cultures. Antidepressants with distinct mechanisms of action, such as clomipramine, duloxetine and fluvoxamine, also increased BDNF mRNA expression in astrocytic and microglial cultures. There are multiple BDNF mRNA variants (exon I, IIA, IV and VI) expressed in astrocytes and microglia and the variant induced by antidepressants has yet to be elaborated. Treatment with antidepressants increased the expression of exon I, IV and VI in astrocyte and microglia. Clomipramine alone significantly upregulated expression of exon IIA. The amitriptyline-induced expression of both total and individual BDNF mRNA variants (exon I, IV and VI) were blocked by MEK inhibitor U0126, indicating MEK/ERK signaling is required in the expression of BDNF. These findings indicate that non-neural cells are a significant target of antidepressants and further support the contention that glial production of BDNF is crucial role in the therapeutic effect of antidepressants. The current data suggest that targeting of glial function could lead to the development of antidepressants with a truly novel mechanism of action.
脑源性神经营养因子（BDNF）此前已被认为在抗抑郁药的治疗效果中发挥重要作用。为了确定抗抑郁药治疗后大脑中产生BDNF的特定细胞类型的作用，研究了三环类抗抑郁药阿米替林对大鼠原代神经元、星形胶质细胞和小胶质细胞皮质培养物的影响。阿米替林增加了星形胶质细胞和小胶质细胞培养物中BDNF mRNA的表达，但未增加神经元培养物中的表达。作用机制不同的抗抑郁药，如氯米帕明、度洛西汀和氟伏沙明，也增加了星形胶质细胞和小胶质细胞培养物中BDNF mRNA的表达。星形胶质细胞和小胶质细胞中表达多种BDNF mRNA变体（外显子I、IIA、IV和VI），抗抑郁药诱导的变体尚未阐明。抗抑郁药治疗增加了星形胶质细胞和小胶质细胞中外显子I、IV和VI的表达。单独使用氯米帕明显著上调外显子IIA的表达。MEK抑制剂U0126阻断了阿米替林诱导的总BDNF mRNA变体和单个BDNF mRNA变体（外显子I、IV和VI）的表达，表明BDNF表达需要MEK/ERK信号传导。这些发现表明非神经细胞是抗抑郁药的重要靶点，并进一步支持了胶质细胞产生BDNF在抗抑郁药治疗效果中起关键作用的观点。目前的数据表明，针对胶质细胞功能可能会导致开发出具有全新作用机制的抗抑郁药。
