Development of anti-Parkinson's disease drugs using P-glycoprotein knockout mice heated with endogenous neurotoxin.

使用内源性神经毒素加热的 P-糖蛋白敲除小鼠开发抗帕金森病药物。

• 批准号: 18390037
• 负责人: OHTA Shigeru
• 金额: $ 10.09万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390037/
• 关键词: parkinsonism; tetrahydroisoquinoline; P-glycoprotein; neurotxin; prodrug

The purpose of this research is to find anti-Parkinson's disease agent from 1-methyl-tetrahydroisoquinoline derivatives. Hydroxy derivatives have high effect, but they are difficult to penetrate of blood-brain barrier, because of their water solubility.The ester group was introduced to the hydroxylated 1-methyl tetrahydroisoquinoline derivatives. They had better anti-parkinsonism effect than hydroxyl derivatives. The second purpose of this study is the examination of the relationship between parkinsonism and the transport characteristics (influx/outflux) of tetrahydroisoquinolines across the blood-brain barrier. At first, to examine the substrate specificity of tetrahydroisoquinolines as P-glycoprotein (P-gp) substrates.These results indicate that 3',4'DHBnTIQ, an endogenous parkinsonism-inducing neurotoxin, is a P-gp substrate.These results may also suggest that P-gp inactivation and/or dysfunction in the brain are closely related to the induction of Parkinson's disease.

本研究的目的是从1-甲基四氢异喹啉衍生物中寻找抗帕金森病药物。羟基化的1-甲基四氢异喹啉衍生物具有很高的药效，但由于其水溶性，难以透过血脑屏障，因此在羟基化的1-甲基四氢异喹啉衍生物中引入酯基。其抗帕金森病作用优于羟基衍生物。本研究的第二个目的是检查帕金森综合征和四氢异喹啉类药物穿过血脑屏障的转运特性（流入/流出）之间的关系。首先，研究了四氢异喹啉类化合物作为P-糖蛋白（P-gp）底物的特异性，结果表明，内源性帕金森病诱导神经毒素3 '，4' DHBnTIQ是P-gp的底物，提示脑内P-gp失活和/或功能障碍与帕金森病的发生密切相关。

项目成果

Neuroprotective mechanism of 1MeTIQ and its derivatives against glutamate-induced neurotoxicity

1MeTIQ及其衍生物对抗谷氨酸诱导的神经毒性的神经保护机制

• 发表时间: 2006
• 作者: Toshiyuki;Ohsawa;Yaichiro;Kotake;Yusuke;Nakatsu;Katsuhiro;Okuda;Shigeru;Ohta
• 通讯作者: Ohta

Parkinsonism-preventing activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives in C57BL mouse in vivo.

• DOI: 10.1248/bpb.29.1401
• 发表时间: 2006-07
• 期刊: Biological & pharmaceutical bulletin
• 影响因子: 2
• 作者: K. Okuda;Y. Kotake;S. Ohta

Tributyltin-induced cell death is meadiated by calpain in PC12 cells

PC12 细胞中三丁基锡诱导的细胞死亡由钙蛋白酶介导

• 发表时间: 2006
• 期刊: Neurotoxicology 27
• 作者: Yusuke;Nakatsu;Yaihchiro;Kotake;Shigeru;Ohta
• 通讯作者: Ohta

Cytotoxicity of 17 tetrahydroisoquinoline derivatives in SH-SY5Y human neuroblastoma cells is related to mitochondria)NADH-ubiquinone oxidoreductase inhibition.

17种四氢异喹啉衍生物对SH-SY5Y人神经母细胞瘤细胞的细胞毒性与线粒体NADH-泛醌氧化还原酶抑制有关。

• 发表时间: 2007
• 期刊: Neurotoxicology 28
• 作者: Y. Kotake;et. al.
• 通讯作者: et. al.

Concentration dependence of the mechanisms of tributyltin-induced apoptosis

• DOI: 10.1093/toxsci/kfm039
• 发表时间: 2007-06-01
• 期刊: TOXICOLOGICAL SCIENCES
• 影响因子: 3.8
• 作者: Nakatsu, Yusuke;Kotake, Yaichiro;Ohta, Shigeru
• 通讯作者: Ohta, Shigeru