Neuroprotective effects of (arylthio)cyclopentenone derivatives on manganese-induced apoptosis in PC12 cells
Neuroprotective effects of (arylthio)cyclopentenone derivatives on manganese-induced apoptosis in PC12 cells
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DOI：
10.1016/j.brainres.2009.07.059
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发表时间：
2009-10-06
期刊：
影响因子：
2.9
通讯作者：
Hirata, Yoko
中科院分区：
文献类型：
--
作者：
Shibata, Shoko;Maeda, Masahide;Hirata, Yoko
帕金森氏病的特征是黑质中多巴胺能神经元的变性。慢性锰中毒与帕金森氏病有许多共同的特征，并且由于中枢神经系统中的多巴胺耗竭，还诱导类似于帕金森氏病的锥体外系综合征。本研究旨在通过鉴定抑制锰诱导的细胞凋亡的化合物来开发新的神经保护药物。在这里，我们报告，（芳硫基）环戊烯酮衍生物，这是合成的类似物的环戊烯酮arylandins，防止锰诱导的PC 12细胞凋亡。半胱天冬酶-3/7活性的高灵敏度测定用于筛选新合成的前列腺素类似物。结果显示，一些环戊烯酮衍生物（GIF-0642、GIF-0643、GIF-0644、GIF-0745和GIF-0747）以浓度依赖性方式抑制锰诱导的caspase-3/7活化。有效的化合物都有一个芳硫基，表明这种结构在（芳硫基）环戊烯酮衍生物的抗凋亡作用中起着重要的作用。通过验证这些化合物抑制锰诱导的DNA片段化和半胱天冬酶-9活化的能力，证实了这些化合物的抗凋亡作用。此外，GIF-0747阻止锰诱导的细胞色素c从线粒体释放。这些结果表明，（芳硫基）环戊烯酮衍生物可能是很好的候选人，用于治疗神经退行性疾病。(C)2009爱思唯尔有限公司版权所有。
Parkinson's disease is characterized by degeneration of dopaminergic neurones in the substantia nigra. Chronic manganese poisoning shares many features of Parkinson's disease, and also induces extrapyramidal syndromes that resemble those of Parkinson's disease due to dopamine depletion in the central nervous system. This study was under-taken to develop novel neuroprotective drugs via the identification of compounds that inhibit manganese-induced apoptosis. Here, we report that (arylthio)cyclopentenone derivatives, which are synthetic analogs of cyclopentenone prostaglandins, prevent manganese-induced apoptosis in PC12 cells. A highly sensitive assay of caspase-3/7 activity was used for screening newly synthesized prostaglandin analogs. The results showed that some cyclopentenone derivatives (GIF-0642, GIF-0643, GIF-0644, GIF-0745, and GIF-0747) inhibit manganese-induced caspase-3/7 activation in a concentration-dependent manner. Effective compounds all have an arylthio group, indicating that this structure plays an important role in the anti-apoptotic effects of (arylthio)cyclopentenone derivatives. The anti-apoptotic effects of these compounds were confirmed by verifying their ability to inhibit the DNA fragmentation and caspase-9 activation induced by manganese. Furthermore, GIF-0747 prevented manganese-induced cytochrome c release from mitochondria. These results suggest that (arylthio)cyclopentenone derivatives may be good candidates for treating neurodegenerative diseases. (C) 2009 Elsevier B.V. All rights reserved.