| Project/Area Number |
17590878
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Okayama University |
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Principal Investigator |
ASANUMA Masato Okayama University, Graduate School of Medicine, Dentistry and Pharmaceut. Sci., Dept. of Brain Science, Associate Professor (00273970)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAZAKI Ikuko Okayama University, Graduate School of Medicine, Dentistry and Pharmaceut. Sci. Dept. of Brain Science, Assistant Professor (40335633)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | PARKINSON'S DISEASE / DOPAIVHNE / DOPAMINE QUINONE / INTERACTING MOLECULE / NEURODEGENERATION / GLUTATHIONE / ASTROGLIAL CELL / ドパミン / ドパミンキノン |
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| Research Abstract |
To clarify the possible roles of dopamine neuron-specific degenerative factor dopamine quinone in the pathogenesis of Parkinson's disease and to investigate therapeutic application of the dopamine quinone-regulating agents, we performed following experiments using dopaminergic neuronal cultured cells and hemi-parkinsonian model mice.
1. Screening of interacting molecules with dopamine or dopamine quinone
By electron spin resonance method using in vitro dopamine quinone generating system, we identified metallothionein-1, some dopamine agonists and certain drug as dopamine quinone-interacting molecules.
2. Dopamine quinone-induced toxicity in cultured neuronal cells and effects of regulation of quinone-quenching system
In dopaminergic CATH.a cells, dopamine quinone generated from excess free dopamine exerts neurotoxic effects. However, the dopamine-quinone-induced neurotoxicity was prevented by quenching of dopamine quinone, e.g. quinone reductase inducer, metallothionein inducer and a drug
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which enhances up-take of the substrate of glutathione synthesis in astroglial cells.
3. Changes in quinone-quenching system and effects of its regulation in parkinsonian animal models
Several molecules of quinone-quenching system were activated in the lesioned striatum of hemi-parkinsonian mice. The drug, which interacts with dopamine quinone, enhanced astroglial proliferation, up-take of glutathione substrate in astroglial cells, and increased glutathione levels in the striatum. Furthermore, the drug ameliorated dopaminergic neuronal loss in the substantia nigra and inhibited repeated L-DOPA injections-induced elevation of protein-bound quinone (quinoprotein) in the striatum. Repeated L-DOPA administration markedly elevated striatal quinoprotein levels and reduced the dopaminergic nerve terminals specifically on the lesioned side in metallothionein-knockout parkinsonian mice, suggesting that intrinsic cysteine-rich molecule metallothionein protects against L-DOPA-induced dopamine quinone neurotoxicity in parkinsonian mice by its quinone-quenching property.
These experimental results suggest a therapeutic potency of dopamine quinone-quenching agents for the patients of Parkinson's disease, and clarify that neuro-glial interaction on up-take of the substrate of glutathione synthesis plays a role in neuroprotective strategies against progressive dopaminergic neurodegeneration. Less
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