Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson's disease and stroke model rats
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概要
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Background: 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. Results: 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. Conclusions: 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.
- 2011-07-08
著者
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Takata Kazuyuki
Faculty Of Pharmaceutical Sciences Hoshi University
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Takahashi Kazunori
京都薬科大学 病態生理学
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Takeuchi Kosei
Kan Research Institute Inc. Kobe Mi R&d Center
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Kanai Yoshihito
Department Of Pharmaceutical Care And Health Sciences Okayama University Graduate School Of Medicine
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Kitamura Yoshihisa
Department Of Neurobiology Kyoto Pharmaceutical University
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Kitamura Yoshihisa
Department Of Pharmacology Research Institute For Wakan-yaku Toyama Medical And Pharmaceutical Unive
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Kitamura Y
Department Of Neurobiology Kyoto Pharmaceutical University
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Kitamura Y
Shimizu Pharmaceutical Co. Ltd. Shizuoka Jpn
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Ariga Hiroyoshi
Laboratory Of Molecular Biolgy Graduate School Of Pharmaceutical Sciences Hokkaido University
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Maita Hiroshi
Graduate School Of Pharmaceutical Sciences Hokkaido University
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Ariga H
Graduate School Of Pharmaceutical Sciences Hokkaido University
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