Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson's Disease In Vitro and In Vivo
Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson's Disease In Vitro and In Vivo
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四甲基吡嗪类似物 T-006 在体外和体内对 6-羟基多巴胺诱导的帕金森病具有神经保护作用
DOI：
10.1155/2019/8169125
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发表时间：
2019-11
影响因子：
--
通讯作者：
Simon Ming-Yuen Lee
中科院分区：
文献类型：
--
作者：
Hefeng Zhou;Min Shao;Xuanjun Yang;Chuwen Li;Guozhen Cui;Cheng Gao;Lijun Di;Hanbing Zhong;Yuqiang Wang;Zaijun Zhang;Simon Ming-Yuen Lee
帕金森病（Parkinson's disease，PD）是一种以黑质多巴胺能神经元进行性缺失为特征的神经退行性疾病，目前尚无治愈方法。我们先前已经报道了四甲基吡嗪（TMP）衍生物T-006在阿尔茨海默病（AD）模型中表现出有益的作用。然而，其对PD的影响尚不清楚。在本研究中，我们在体内和体外PD模型中研究了T-006对6-羟基多巴胺（6-OHDA-）诱导的损伤的神经保护作用和潜在机制。我们的研究结果表明，T-006减轻了6-OHDA诱导的PC 12细胞线粒体膜电位损失，恢复了能量代谢和线粒体生物合成。此外，动物实验表明，给予T-006可显著减弱6-OHDA诱导的SNpc中酪氨酸羟化酶（TH-）阳性神经元以及纹状体中多巴胺能神经纤维的丢失，并增加纹状体中多巴胺及其代谢产物（DOPAC、HVA）的浓度。在6-OHDA损伤小鼠中，T-006治疗后功能缺陷得到恢复，表现为运动协调和旋转行为改善。此外，我们发现T-006的神经保护作用至少部分是通过PKA/Akt/GSK-3β和CREB/PGC-1α/NRF-1/TFAM通路的激活介导的。综上所述，我们的研究结果表明，T-006可以被开发为一种新的神经保护剂，PD的两个途径可能是有前途的治疗靶点。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer's disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.
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影响因子：
3.1
作者：
Chen, Hai-Yun;Xu, Da-Ping;Wang, Yu-Qiang
通讯作者：
Wang, Yu-Qiang
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1201/b12952-20
发表时间：
2021-04
期刊：
The Lancet
影响因子：
--
作者：
B. Bloem;M. Okun;C. Klein
通讯作者：
B. Bloem;M. Okun;C. Klein
影响因子：
16.6
作者：
Hasegawa K;Yasuda T;Shiraishi C;Fujiwara K;Przedborski S;Mochizuki H;Yoshikawa K
通讯作者：
Yoshikawa K
α-突触核蛋白与TOM20结合，并抑制在帕金森氏病中进口的线粒体蛋白。
影响因子：
17.1
作者：
Di Maio R;Barrett PJ;Hoffman EK;Barrett CW;Zharikov A;Borah A;Hu X;McCoy J;Chu CT;Burton EA;Hastings TG;Greenamyre JT
通讯作者：
Greenamyre JT