| Project/Area Number |
11670629
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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 |
OGAWA Norio Graduate School of Medicine and Dentistry, Okayama University, Professor, 大学院・医歯学総合研究科, 教授 (90033208)
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| Co-Investigator(Kenkyū-buntansha) |
ASANUMA Masato Graduate School of Medicine and Dentistry, Okayama University, Associate Professor, 大学院・医歯学総合研究科, 助教授 (00273970)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | METALLOTHIONEIN / PARKINSON'S DISEASE / 6-HYDROXYDOPAMINE / LEVODOPA / OXIDATIVE STRESS / AGING / DOPAMINE / DIFFERENTIATION / メタロチオメイン / 神経成長抑制因子 / メタロチオメインーIII / 核内移行 / メタロチオメイン-III |
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| Research Abstract |
To clarify the function, role and involvement of metallothionein (MT), especially MT-III, in parkinsonian and aged, we investigated the expression and function of MT-III, and changes in MT with the treatment of dopaminergic drugs, oxidative stress and aging, as follows:
1. Expression of MT-III mRNA in the brain of animal models of Parkinson's disease
Levodopa-induced increase in MT-III mRNA which shown in the contralateral side of the striatum was not seen in the ipsilateral side of the striatum in hemi-parkinsonian rats which lesioned by 6-hydroxydopamine (6-OHDA), suggesting that low inducibility of MT-III by levodopa treatment in the parkinsonian brain aggravates the disease through generation of oxidative stress.
2. Effects of aging and inflammatory stress on MT-III expression in the brain
The treatment of an endotoxin lipopolysaccaride which produces inflammation markedly induced increases in MT-III expression, especially in the oligodendroglial cells and the microglial cells, in the young-adult rat brain regions. However, the treatment of the toxin did not increase rather suppress MT-III expression in the aged rat brain, suggesting that the responsibility of brain MT-III against oxidative stress is decreased as aging.
3. MT-III expression and its subcellular localization in the differenciated dopaminergic cells
The treatment of differentiating reagent increased MT-III expression in dopaminergic cells. Furthermore, we clarified that MT-III was translocated into the nucleus in the differentiated dopaminergic cells when additional treatment of brain extract produced apoptotic cell death.
4. Dopaminergic lesions by 6-OHDA in metallothionein-I and -II knock-out mice brain
The loss of nigral dopamine neurons induced by the 6-OHDA injection was significantly aggravated in the MT-I, II knock-out mice, suggest that MT-I and -II exert neuroprotective effects against the dopaminergic neurotoxicity of 6-OHDA in the substantia nigra.
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