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博士論文
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Characterization of imatinib as an anti-parkinsonian agent in mouse models of Parkinson's disease
- 国立国会図書館永続的識別子
- info:ndljp/pid/11711332
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一般注記:
- Parkinson's disease (PD) is caused by a progressive degeneration of nigral dopaminergic neurons leading to striatal dopamine deficiency. In the clinic...
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デジタル
- 資料種別
- 博士論文
- タイトル
- 著者・編者
- Zhou, Yu
- 著者標目
- 出版年月日等
- 2020-03-23
- 出版年(W3CDTF)
- 2020-03-23
- 並列タイトル等
- パーキンソン病モデルマウスにおけるイマチニブの薬効評価
- 授与機関名
- 徳島大学
- 授与年月日
- 2020-03-23
- 授与年月日(W3CDTF)
- 2020-03-23
- 報告番号
- 甲第3385号
- 学位
- 博士(薬科学)
- 博論授与番号
- 甲第3385号
- 本文の言語コード
- eng
- 対象利用者
- 一般
- 一般注記
- Parkinson's disease (PD) is caused by a progressive degeneration of nigral dopaminergic neurons leading to striatal dopamine deficiency. In the clinic, administration of dopamine precursor levodopa is the gold standard for the treatment of PD. However, long-term exposure to levodopa often causes side effects, such as levodopa-induced dyskinesia. So development of new therapeutic agents for motor deficits is needed in the treatment of PD. In the last decade, an abnormal activity of the Abelson non-receptor tyrosine kinase (c-Abl) was proved relating to the degeneration of nigral dopaminergic cells in PD. Thereby it has been expected that the inhibition of c-Abl activity would exert anti-parkinsonian effects. Moreover, it has also been reported that a c-Abl inhibitor nilotinib showed acute therapeutic potency on motor symptoms in a PD mouse model, possibly with affecting signaling mechanisms in striatum.Imatinib, as a c-Abl inhibitor, is currently approved for tumor related diseases such as human chronic myelogenic leukemia, gastrointestical stromal tumor and Philadelphia chromosome positive acute lymphoblastic leukemia in clinical use. To examine its potential as a PD therapeutic in this study, I evaluated imatinib in two types of PD models of mice: systemically MPTP-induced PD model mice, and unilaterally 6-hyroxydopamine (6-OHDA)-lesioned hemiparkinsonian mice.When imatinib was systemically administered, the striatum-to-blood concentration ratio of it was about 8%, indicating that peripherally administered imatinib was partially incorporated into the striatum. In MPTP mice, behavioral analysis revealed that a single dose of imatinib (25 mg/kg) could significantly normalized MPTP-induced motor deficits. In western-blot analysis, imatinib significantly reduced the expression of cyclin-dependent kinase 5 (Cdk5) phosphorylated at tyrosine 15 residue (Cdk5-pTyr15) and dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) phosphorylated at threonine 75 residue (DARPP-32-pThr75) in striatum, which were increased by MPTP treatment than normal mice. Moreover, I examined the combinatory effects of imatinib and levodopa. Combination of low doses of imatinib (10 mg/kg) and levodopa (5 mg/kg), which were not effective when solely applied, significantly improved the motor activity of MPTP mice in behavioral tests. In western-blot analysis, the expression of active c-Abl phosphorylated at tyrosine 412 residue (c-Abl-pTyr412), Cdk5-pTyr15 and DARPP-32-pThr75 were also significantly reduced by this combination. These results strongly suggest symptomatic effects of acute imatinib treatment on motor deficits in MPTP mice.I further evaluated imatinib in 6-OHDA-lesioned hemiparkinsonian mice. Essentially, therapeutic effects of imatinib were also obtained on motor deficits and biochemical changes in this model, which were comparable with the results obtained in MPTP model.Based on above results, regulating c-Abl/Cdk5/DARPP-32-Thr75 signaling pathway would be important when considering the pathophysiology of motor dysfunctions in PD. I suggest the possibility of a c-Abl inhibitor imatinib as a novel and effective therapeutic agent to treat PD.
- 国立国会図書館永続的識別子
- info:ndljp/pid/11711332
- コレクション(共通)
- コレクション(障害者向け資料:レベル1)
- コレクション(個別)
- 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
- 収集根拠
- 博士論文(自動収集)
- 受理日(W3CDTF)
- 2021-08-09T17:15:52+09:00
- 記録形式(IMT)
- application/pdf
- オンライン閲覧公開範囲
- 国立国会図書館内限定公開
- デジタル化資料送信
- 図書館・個人送信対象外
- 遠隔複写可否(NDL)
- 可
- 連携機関・データベース
- 国立国会図書館 : 国立国会図書館デジタルコレクション