Lee Heejin, Kim Hyun-Jin, Min Ju-Sik, Lee Eunhye, Choi Dong Kyu, Choi Jae-Hyeog, Seo Yohan, Lee Sion, Im Chun Young, Bae Gi Hun, Oh Yoojin, Ko Eun-A, Jung Sung-Cherl, Kim Soong-Hyun, Kwon Oh-Bin
New Drug Development Center, Daegu, Korea.
Salk Institute for Biological Studies, La Jolla, California, USA.
Pharmacol Res Perspect. 2025 Feb;13(1):e70057. doi: 10.1002/prp2.70057.
Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.
多巴胺的氧化会导致各种副作用，最终导致细胞死亡并促使帕金森病（PD）的发生。为了对抗多巴胺氧化，新合成的多巴胺会通过囊泡单胺转运体2（VMAT2）迅速转运到囊泡中进行储存。PD患者的VMAT2表达会降低，并且研究表明，VMAT2表达低的动物体内多巴胺氧化产物和α-突触核蛋白的积累会增加。相反，过度表达VMAT2的动物对多巴胺能神经元表现出更好的保护作用。基于这些发现，本研究使用组蛋白去乙酰化酶抑制剂（HDACi）来增加VMAT2的表达，降低多巴胺诱导的氧化应激，并在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD动物模型中评估由此产生的行为改善情况。LMK-235不仅在分化为多巴胺能细胞的SH-SY5Y细胞系中，在不同浓度下都增加了VMAT2的表达，而且在几种毒性试验中都表现出了有效的细胞保护特性。在MPTP诱导的PD模型的纹状体和腹侧被盖区，它都显著提高了VMAT2的表达，支持了其在逆转与PD相关的行为异常中的作用。除了这些结果外，将LMK-235与PD的标准疗法左旋多巴联合使用，恢复了典型的行为模式，突出了HDACi在缓解PD症状方面的潜力。主要在神经系统中发现的IIa类组蛋白去乙酰化酶抑制剂LMK-235诱导的VMAT2表达，有助于将多巴胺隔离到囊泡中，通过抑制多巴胺氧化可能增强细胞存活。此外，VMAT2的上调已被证明能有效抵抗MPTP诱导的毒性，并显著改善与PD相关的行为异常。与左旋多巴联合使用在行为结果方面产生了最显著的改善。总之，这些发现表明，VMAT2的过度表达可能为开发治疗PD的方法提供一个有前景的策略，即减轻由多巴胺氧化导致的多巴胺能神经元死亡。
