Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson's disease and stroke model rats.
Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson's disease and stroke model rats.
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DOI：
10.1186/1750-1326-6-48
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发表时间：
2011-07-08
影响因子：
15.1
通讯作者：
Ariga H
中科院分区：
文献类型：
--
作者：
Kitamura Y;Watanabe S;Taguchi M;Takagi K;Kawata T;Takahashi-Niki K;Yasui H;Maita H;Iguchi-Ariga SM;Ariga H
帕金森病（PD）和脑缺血分别是慢性和急性神经退行性疾病，并且认为这些疾病的发作至少由氧化应激诱导。PD是由黑质和纹状体中多巴胺水平降低引起的，而脑缺血是由于局部血液供应减少或停止而发生的。尽管多巴胺的前体和多巴胺降解的抑制剂已用于PD治疗，并且抗氧化剂已用于脑缺血治疗，但在治疗期间细胞死亡进展。因此，预防氧化应激诱导的细胞死亡的试剂对于PD和脑缺血的基本疗法是必需的。DJ-1是PD家族形式PARK 7的致病基因产物，在转录调节和抗氧化应激中起作用，其功能的丧失被认为导致PD的发作。在DJ-1的氨基酸106（C106）处的半胱氨酸的超氧化使得DJ-1失活，并且已经在具有散发形式的PD的患者中观察到这种氧化的DJ-1。在这项研究中，通过虚拟筛选分离出与DJ-1结合的化合物comp-23。化合物-23阻止了SH-SY 5 Y细胞和腹侧中脑的原代神经元细胞的氧化应激诱导的死亡，但不能阻止DJ-1敲低的SH-SY 5 Y细胞的氧化应激诱导的死亡，表明化合物的作用对DJ-1是特异性的。化合物-23抑制由氧化应激诱导的活性氧簇（ROS）的产生并防止DJ-1的过度氧化。此外，comp-23防止黑质中的多巴胺能细胞死亡，并恢复6-羟基多巴胺注射和鱼藤酮治疗的PD模型大鼠和小鼠的运动异常。化合物-23还减少了由大脑中动脉闭塞诱导的大鼠脑缺血的梗塞面积。comp-23的保护活性似乎比先前鉴定的化合物B的保护活性更强。结果表明，comp-23通过减少ROS介导的神经元损伤发挥神经保护作用，表明comp-23成为PD和缺血性神经变性治疗的先导化合物。
Parkinson's disease (PD) and cerebral ischemia are chronic and acute neurodegenerative diseases, respectively, and onsets of these diseases are thought to be induced at least by oxidative stress. PD is caused by decreased dopamine levels in the substantia nigra and striatum, and cerebral ischemia occurs as a result of local reduction or arrest of blood supply. Although a precursor of dopamine and inhibitors of dopamine degradation have been used for PD therapy and an anti-oxidant have been used for cerebral ischemia therapy, cell death progresses during treatment. Reagents that prevent oxidative stress-induced cell death are therefore necessary for fundamental therapies for PD and cerebral ischemia. DJ-1, a causative gene product of a familial form of PD, PARK7, plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to result in the onset of PD. Superfluous oxidation of cysteine at amino acid 106 (C106) of DJ-1 renders DJ-1 inactive, and such oxidized DJ-1 has been observed in patients with the sporadic form of PD. In this study, a compound, comp-23, that binds to DJ-1 was isolated by virtual screening. Comp-23 prevented oxidative stress-induced death of SH-SY5Y cells and primary neuronal cells of the ventral mesencephalon but not that of DJ-1-knockdown SH-SY5Y cells, indicating that the effect of the compound is specific to DJ-1. Comp-23 inhibited the production of reactive oxygen species (ROS) induced by oxidative stress and prevented excess oxidation of DJ-1. Furthermore, comp-23 prevented dopaminergic cell death in the substantia nigra and restored movement abnormality in 6-hydroxyldopamine-injected and rotenone-treated PD model rats and mice. Comp-23 also reduced infarct size of cerebral ischemia in rats that had been induced by middle cerebral artery occlusion. Protective activity of comp-23 seemed to be stronger than that of previously identified compound B. The results indicate that comp-23 exerts a neuroprotective effect by reducing ROS-mediated neuronal injury, suggesting that comp-23 becomes a lead compound for PD and ischemic neurodegeneration therapies.
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DOI：
10.1074/jbc.m110.137034
发表时间：
2010-12-17
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ishikawa S;Taira T;Takahashi-Niki K;Niki T;Ariga H;Iguchi-Ariga SM
通讯作者：
Iguchi-Ariga SM
影响因子：
4.8
作者：
Honbou, K;Suzuki, NN;Inagaki, F
通讯作者：
Inagaki, F
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
DOI：
10.1073/pnas.0607260103
发表时间：
2006-10-10
影响因子：
11.1
作者：
Clements, Casey M.;McNally, Richard S.;Ting, Jenny P-Y.
通讯作者：
Ting, Jenny P-Y.
影响因子：
6.3
作者：
Sakurai, Masahiro;Kawamura, Takae;Abe, Koji
通讯作者：
Abe, Koji