New Drug Development Center, K-Medihub, Daegu, Korea.
Department of Physiology, School of Medicine, Jeju National University, Jeju, Korea.
Pharmacol Res Perspect. 2023 Oct;11(5):e01135. doi: 10.1002/prp2.1135.
The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being studied. Moreover, the development of disease treatments using histone deacetylase (HDAC) inhibitors (HDACi) is actively progressing in various fields. Recently, research on the possibility of regulating neuropsychiatric disorders has been conducted. In this study, we evaluated whether VMAT2 expression increased by an HDACi can fine-tune neuropsychotic behavior, such as attention deficit hyperactivity disorder (ADHD) and protect against the cell toxicity through oxidized dopamine. First, approximately 300 candidate HDACi compounds were added to the SH-SY5Y dopaminergic cell line to identify the possible changes in the VMAT2 expression levels, which were measured using quantitative polymerase chain reaction. The results demonstrated, that treatment with pimelic diphenylamide 106 (TC-H 106), a class I HDACi, increased VMAT2 expression in both the SH-SY5Y cells and mouse brain. The increased VMAT2 expression induced by TC-H 106 alleviated the cytotoxicity attributed to 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP ) and free dopamine treatment. Moreover, dopamine concentrations, both intracellularly and in the synaptosomes, were significantly elevated by increased VMAT2 expression. These results suggest that dopamine concentration regulation by VMAT2 expression induced by TC-H 106 could alter several related behavioral aspects that was confirmed by attenuation of hyperactivity and impulsivity, which were major characteristics of animal model showing ADHD-like behaviors. These results indicate that HDACi-increased VMAT2 expression offers sufficient protections against dopaminergic cell death induced by oxidative stress. Thus, the epigenetic approach could be considered as therapeutic candidate for neuropsychiatric disease regulation.
囊泡单胺转运体 2（VMAT2）在多巴胺调节中的重要性，这被认为对神经精神疾病至关重要，目前正在研究中。此外，使用组蛋白去乙酰化酶（HDAC）抑制剂（HDACi）开发疾病治疗方法在各个领域也在积极推进。最近，研究了调节神经精神疾病的可能性。在这项研究中，我们评估了 HDACi 增加的 VMAT2 表达是否可以微调神经精神行为，如注意力缺陷多动障碍（ADHD），并通过氧化多巴胺来保护细胞免受毒性影响。首先，将大约 300 种候选 HDACi 化合物添加到 SH-SY5Y 多巴胺能细胞系中，以确定 VMAT2 表达水平的可能变化，并用定量聚合酶链反应测量。结果表明，用 I 类 HDACi 皮米酸二苯酰胺 106（TC-H 106）处理可增加 SH-SY5Y 细胞和小鼠大脑中的 VMAT2 表达。TC-H 106 诱导的 VMAT2 表达增加减轻了 6-羟多巴胺（6-OHDA）或 1-甲基-4-苯基吡啶（MPP）和游离多巴胺处理引起的细胞毒性。此外，细胞内和突触小体中的多巴胺浓度也因 VMAT2 表达的增加而显著升高。这些结果表明，TC-H 106 诱导的 VMAT2 表达调节多巴胺浓度可能会改变几个相关的行为方面，这通过减轻多动和冲动行为得到了证实，多动和冲动行为是表现出 ADHD 样行为的动物模型的主要特征。这些结果表明，HDACi 增加的 VMAT2 表达对氧化应激诱导的多巴胺能细胞死亡提供了足够的保护。因此，表观遗传方法可以被认为是神经精神疾病调节的治疗候选物。
