Elucidation of multiple actions of reactive nitrogen species in degeneration of midbrain dopaminergic neurons
| Project/Area Number |
16590048
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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 |
Biological pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
KATSUKI Hiroshi KYOTO UNIVERSITY, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (40240733)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Neurodegenerative disorder / Parkinson disease / Oxidative stress / Nitric oxide / Nitrotyrosine / Thrombin / Inflammatory response |
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| Research Abstract |
With special reference to the actions of reactive nitrogen species and related compounds, this study addressed the roles of oxidative stress in induction of selective degeneration of midbrain nigral dopaminergic neurons, a hallmark of Parkinson disease pathology. (1) Activation of microgia in midbrain slice cultures by lipopolysaccharide induced degeneration of dopaminergic neurons, which was mediated by increases in expression of inducible nitric oxide (NO) synthase and production of NO. Dismutation of superoxide did not inhibit induction of neuronal death, whereas a JNK inhibitor and α-tocopherol protected dopaminerguc neurons without affecting NO production. On the other hand, degeneration of dopaminergic neurons induced by application of thrombin to midbrain slice cultures was associated with activation of multiple MAP kinase family members and a subsequent increase in expression of NO synthase. Inhibition of these enzymes as well as depletion of microglia markedly suppressed dopaminergic neurodegeneration. Thus, thrombin was suggested to exert selective dopaminergic neurotoxicity via microglial activation and increased NO production. (2) 3-Nitrotyrosine (3-NT), which is formed by reaction of tyrosine with NO-related molecular species, induced degeneration of midbrain dopaminergic neurons in culture. Cellular uptake of 3-NT via amino acid transporters was essential for induction of cell death, and 3-NT promoted superoxide production in cells, suggesting that 3-NT promotes degeneration of dopaminergic neurons by acting as an intracellular superoxide generator. (3) Knockdown of DJ-1, a protein encoded by a gene responsible for familial Parkinson disease, rendered SH-SY5Y cells vulnerable to several agents including 6-OHDA, H_2O_2 and an NO donor. In addition, treatment of SH-SY5Y cells and C6 cells with H_2O_2 increased expression of DJ-1, suggesting that DJ-1 functions as a part of endogenous protective mechanisms against oxidative stress.
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Report
(3 results)
Research Products
(50 results)
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[Journal Article] Effects of R-(-)-BPAP on the expressions of neurotrophins and their receptors in mesencephalic slices.2005
Author(s)
Hirami, C., Takahata, K., Shimazu, S., Yoneda, F., Hayashi, K., Katsuki, H., Akaike, A.
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Journal Title
Biol.Pharm.Bull. 28(8)
Pages: 1524-2526
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] p-Quinone mediates 6-hydroxydopomine-induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p-quinone into melanin extracellularly.2005
Author(s)
Izumi, Y., Sawada, H., Sakka, N., Yamamoto, N., Kume, T., Katsuki, H., Shimohama, S., Akaike, A.
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Journal Title
J.Neurosci.Res. 79(6)
Pages: 849-860
Description
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[Journal Article] Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells.2005
Author(s)
Izumi, Y., Sawada, H., Yamamoto, N., Kume, T., Katsuki, H., Shimohama, S., Akaike, A.
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Journal Title
J.Neurosci.Res. 82(1)
Pages: 126-137
Description
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[Journal Article] Protective effect of serofendic acid on glutamate-induced neurotoxicity in rat cultured motor neurons.2005
Author(s)
Kume, T., Kawai, Y., Yoshida, K., Nakamizo, T., Kanki, R., Sawada, H., Katsuki, H., Shimohama, S., Sugimoto, H., Akaike, A.
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Journal Title
Neurosci.Lett. 383(3)
Pages: 199-202
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons.2005
Author(s)
Kume, T., Sugimoto, M., Takada, Y., Yamaguchi, T., Yonezawa, A., Katsuki, H., Sugimoto, H., Akaike, A.
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Journal Title
Eur.J.Pharmacol. 527(1-3)
Pages: 77-85
Description
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[Journal Article] α-Tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons.2004
Author(s)
Osakada, F., Hashino, A., Kume, T., Katsuki, H., Kaneko, S., Akaike, A.
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Journal Title
Neuropharmacology 47(6)
Pages: 904-915
Description
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[Journal Article] Serofendic acid, a sulfur-containing diterpenoid derived from fetal calf serum, attenuates reactive oxygen species-induced oxidative stress in cultured striatal neurons.2004
Author(s)
Osakada, F., Kawato, Y., Kume, I., Katsuki, H., Sugimoto, H., Akaike, A.
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Journal Title
J.Pharmacol.Exp.Ther. 311(1)
Pages: 51-59
Description
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