通过I类HDAC抑制剂TC-H 106表达VMAT2来保护多巴胺能细胞和减轻神经精神疾病症状。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Heejin Lee, Hye-Ji Kim, Dong-Kyu Choi, Eu N-A Ko, Jae-Hyeog Choi, Yohan Seo, Sion Lee, Soong-Hyun Kim, Sejin Jung, Minwoo Kim, Dongwan Kang, Chun-Young Im, Gi-Hun Bae, Sung-Cherl Jung, Oh-Bin Kwon
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引用次数: 0

摘要

膀胱单胺类转运蛋白2(VMAT2)在多巴胺调节中的重要性目前正在研究中,多巴胺调节被认为对神经精神疾病至关重要。此外,使用组蛋白脱乙酰酶(HDAC)抑制剂(HDACi)治疗疾病的开发在各个领域都取得了积极进展。最近,对调节神经精神障碍的可能性进行了研究。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),并通过氧化多巴胺保护细胞免受细胞毒性。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,这是使用定量聚合酶链式反应测量的。结果表明,用一类I类HDACi庚二酸二苯胺106(TC-H 106)处理,增加了SH-SY5Y细胞和小鼠脑中VMAT2的表达。TC-H 106诱导的VMAT2表达增加减轻了归因于6-羟基多巴胺(6-OHDA)或1-甲基-4-苯基吡啶鎓(MPP+)和游离多巴胺处理的细胞毒性。此外,细胞内和突触体中的多巴胺浓度都因VMAT2表达的增加而显著升高。这些结果表明,TC-H 106诱导的VMAT2表达对多巴胺浓度的调节可以改变几个相关的行为方面,多动症和冲动性的减弱证实了这一点,这是表现出多动症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,表观遗传学方法可以被认为是神经精神疾病调节的候选治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106.

Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106.

Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106.

Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106.

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.

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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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