2002 Fiscal Year Final Research Report Summary
Initiating and preventing factors in neurodegeneration underlying Parkinson's disease
| Project/Area Number |
12672205
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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 |
応用薬理学・医療系薬学
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| Research Institution | Asahikawa Medical College |
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Principal Investigator |
MATSUBARA Kazuo Asahikawa Med. College, Department of Hospital Pharmacy & Pharmacology, 医学部, 教授 (20127533)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMIZU Keiko Asahikawa Med. College, Department of Legal Medicine, 医学部, 助教授 (90312462)
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| Project Period (FY) |
2000 – 2002
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| Keywords | Parkinson's disease / Paraquat / Organotypic slice cultures / Dopamine receptor agonist / Excitotoxic pathway / Nitrogen oxide / Etiology |
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| Research Abstract |
Paraquat (PQ) is a herbicide to possibly induce Parkinson's disease (PD), since a strong correlation has been found between the incidence of the disease and the amount of paraquat used. In this study, we examined PQ toxicity in rat organotypic midbrain slice cultures. PQ dose dependently reduced the number of dopaminergic neurons in cultured slices. Since this damage was prevented by GBR-12909, the dopamine transporter could be an initial step of the PQ induced dopaminergic neurotoxicity. The sequential treatments with lower PQ and MPP^+ doses, where each dose alone was not lethal, markedly killed dopamine neurons, suggesting that the exposure of a lower dose of PQ could lead to the vulnerability of dopaminergic neurons. This cell death was prevented by the inhibitors of NMDA, nitric oxide synthase (NOS), cycloheximide and caspase cascade. Neurons expressing NOS were identified inside and around the regions where dopamine neurons were packed. The cell death induced by the sequential treatments with PQ and MPP^+ was also rescued by L-deprenyl and dopamine D2/3 agonists. These results strongly support that the constant exposure to low levels of PQ would lead to the vulnerability of dopaminergic neurons in the nigrostriatal system by the excitotoxic pathway, and might potentiate neurodegeneration caused by the exposure of other substances and aging.
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[Publications] A. Storcha, S. Otta, Y-I. Hwanga, R. Ortmannb, A. Heinb, S. Frenzelb, K. Matsubarac, M. A. Collins, S. Ohta, H-U. Wolff, J. Schwarzg: "Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: Studies using heterologous expression systems of the dopamine transporter"Biochemical Pharmacology. 163. 909-920 (2002)
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