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Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson's disease and stroke model rats

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Title: Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson's disease and stroke model rats
Authors: Kitamura, Yoshihisa Browse this author →KAKEN DB
Watanabe, Shotaro Browse this author
Taguchi, Masanobu Browse this author
Takagi, Kentaro Browse this author →KAKEN DB
Kawata, Takuya Browse this author
Takahashi-Niki, Kazuko Browse this author →KAKEN DB
Yasui, Hiroyuki Browse this author →KAKEN DB
Maita, Hiroshi Browse this author →KAKEN DB
Iguchi-Ariga, Sanae M. M. Browse this author →KAKEN DB
Ariga, Hiroyoshi Browse this author →KAKEN DB
Issue Date: 8-Jul-2011
Publisher: BioMed Central
Journal Title: Molecular Neurodegeneration
Volume: 6
Start Page: 48
Publisher DOI: 10.1186/1750-1326-6-48
Abstract: 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.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 有賀 寛芳

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