Abe Hiromi, Hisaoka-Nakashima Kazue, Kajitani Naoto, Okada-Tsuchioka Mami, Yano Ryoya, Itagaki Kei, Shibasaki Chiyo, Morioka Norimitsu, Nakata Yoshihiro, Takebayashi Minoru
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan; Department of Pharmacology, Hiroshima University, Graduate School of Biomedical & Health Sciences, Hiroshima, Hiroshima, Japan.
Department of Pharmacology, Hiroshima University, Graduate School of Biomedical & Health Sciences, Hiroshima, Hiroshima, Japan.
Biochem Biophys Res Commun. 2016 Oct 28;479(4):907-912. doi: 10.1016/j.bbrc.2016.09.070. Epub 2016 Sep 24.
Neurotrophic/growth factors derived from glial cells, especially astrocytes, have been implicated in mood disorders and the pharmacological effects of antidepressant drugs. Previous studies demonstrated that the release of glial cell line-derived neurotrophic factor (GDNF) induced by the tricyclic antidepressant amitriptyline was significantly inhibited by a broad-spectrum matrix metalloproteinase (MMP) inhibitor in rat C6 astroglial cells (C6 cells). However, it is unknown whether amitriptyline affects MMP enzymatic activity or expression, and the MMP subtype has yet to be identified. The current study measured the effect of antidepressants on MMP activity with gelatin zymography, an in vitro assay for enzymatic activity, in C6 cells and primary cultured rat astrocytes (primary astrocytes). Treatment with amitriptyline increased zymographic MMP-9 activity without changing MMP-9 mRNA expression in C6 cells. Several different classes of antidepressants significantly increased zymographic MMP-9 activity in C6 cells and primary astrocytes, whereas antipsychotic drugs without antidepressant pharmacological activity did not. The amitriptyline-induced expression of GDNF mRNA was completely blocked by selective inhibition of MMP-9 in C6 cells. Treatment of C6 cells and primary astrocytes with exogenous recombinant MMP-9 increased GDNF mRNA expression, similar to that observed with amitriptyline. Inhibiting MMP-3 blocked amitriptyline-induced zymographic MMP-9 activation in C6 cells and primary astrocytes, indicating that MMP-3 is necessary for MMP-9 activity. The current study suggests that MMP-9 activation is indispensable in the amitriptyline-induced expression of GDNF mRNA in astrocytes and further supports a role of astrocytic neurotrophic/growth factors in the pharmacological effect of antidepressants.
源自神经胶质细胞，尤其是星形胶质细胞的神经营养/生长因子，与情绪障碍及抗抑郁药物的药理作用有关。先前的研究表明，在大鼠C6星形胶质细胞（C6细胞）中，三环类抗抑郁药阿米替林诱导的胶质细胞源性神经营养因子（GDNF）释放受到广谱基质金属蛋白酶（MMP）抑制剂的显著抑制。然而，尚不清楚阿米替林是否影响MMP的酶活性或表达，且MMP亚型尚未确定。本研究采用明胶酶谱法（一种酶活性的体外检测方法）在C6细胞和原代培养的大鼠星形胶质细胞（原代星形胶质细胞）中测定了抗抑郁药对MMP活性的影响。用阿米替林处理可增加C6细胞中酶谱法检测的MMP-9活性，而不改变MMP-9 mRNA表达。几种不同类型的抗抑郁药可显著增加C6细胞和原代星形胶质细胞中酶谱法检测的MMP-9活性，而无抗抑郁药理活性的抗精神病药物则无此作用。在C6细胞中，选择性抑制MMP-9可完全阻断阿米替林诱导的GDNF mRNA表达。用外源性重组MMP-9处理C6细胞和原代星形胶质细胞可增加GDNF mRNA表达，与阿米替林处理后的情况相似。抑制MMP-3可阻断阿米替林诱导的C6细胞和原代星形胶质细胞中酶谱法检测的MMP-9激活，表明MMP-3对MMP-9活性是必需的。本研究表明，MMP-9激活在阿米替林诱导的星形胶质细胞中GDNF mRNA表达中不可或缺，并进一步支持星形胶质细胞神经营养/生长因子在抗抑郁药药理作用中的作用。
