Muñoz-Cobo I, Belloch F B, Díaz-Perdigón T, Puerta E, Tordera R M
Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain.
Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain.
Behav Brain Res. 2017 Sep 29;335:128-131. doi: 10.1016/j.bbr.2017.07.045. Epub 2017 Aug 1.
Some histone deacetylase (HDACs) enzymes have been proposed as epigenetic targets involved in the pathophysiology of depression and antidepressant-like action. Among them, we have recently identified SIRT2, a class III NAD-dependent HDAC, as being oppositely regulated by stress and antidepressants. Moreover, SIRT2 inhibition has shown antianhedonic-like action in the chronic mild stress model of depression. Here we have extended the study using an alternative model of depression based in a genetic manipulation of glutamate function. Specifically, mice heterozygous for the vesicular glutamate transporter 1 (VGLUT1+/-) were used. Firstly, mRNA expression of the different members of the HDAC superfamily in the prefrontal cortex (PFC) of VGLUT1+/- mice and WT littermates were studied by RT-PCR. Secondly, the effect of repeated treatment with the selective SIRT2 inhibitor 33i and the antidepressant imipramine on anhedonic behaviour of VGLUT1+/- mice was studied by weekly monitoring of sucrose intake. Further, the interaction of 33i towards specific monoaminergic targets such as serotonin or noradrenaline transporters as well as the monoaminooxidase enzyme was studied. The mRNA occurance of the different members of HDAC superfamily was not altered in the PFC of VGLUT1+/- mice. While repeated imipramine showed an anti-anhedonic action in both VGLUT1+/- and WT, the selective SIRT2 inhibitor 33i fully reversed anhedonia of VGLUT1+/-. Further, 33i showed no interaction with the above mentioned monoaminergic molecular targets. These results confirm that SIRT2 inhibition is able to reverse anhedonia in different animal models and highlight the need to further investigate the role of SIRT2 inhibitors as new antidepressant agents.
一些组蛋白去乙酰化酶（HDACs）已被提出作为参与抑郁症病理生理学和抗抑郁样作用的表观遗传靶点。其中，我们最近发现Ⅲ类NAD依赖性HDAC的SIRT2受应激和抗抑郁药的反向调节。此外，SIRT2抑制在慢性轻度应激抑郁症模型中显示出抗快感缺失样作用。在此，我们使用基于谷氨酸功能基因操作的另一种抑郁症模型扩展了研究。具体而言，使用了囊泡谷氨酸转运体1（VGLUT1+/-）杂合子小鼠。首先，通过RT-PCR研究了VGLUT1+/-小鼠和野生型同窝小鼠前额叶皮质（PFC）中HDAC超家族不同成员的mRNA表达。其次，通过每周监测蔗糖摄入量，研究了选择性SIRT2抑制剂33i和抗抑郁药丙咪嗪重复治疗对VGLUT1+/-小鼠快感缺失行为的影响。此外，研究了33i与特定单胺能靶点（如5-羟色胺或去甲肾上腺素转运体）以及单胺氧化酶的相互作用。HDAC超家族不同成员的mRNA在VGLUT1+/-小鼠的PFC中未发生改变。虽然重复给予丙咪嗪在VGLUT1+/-和野生型小鼠中均显示出抗快感缺失作用，但选择性SIRT2抑制剂33i完全逆转了VGLUT1+/-小鼠的快感缺失。此外，33i与上述单胺能分子靶点没有相互作用。这些结果证实，SIRT2抑制能够在不同动物模型中逆转快感缺失，并强调需要进一步研究SIRT2抑制剂作为新型抗抑郁药的作用。
