2007 Fiscal Year Final Research Report Summary
Mechanisms and Prevention of Neurodegeneration via Microglial Activation in the Nigro-Striatal System
| Project/Area Number |
18590052
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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 | Kumamoto University (2007)
Kyoto University (2006) |
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Principal Investigator |
KATSUKI Hiroshi Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Professor (40240733)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Parkinson disease / Dopamine neuron / Retinoid / Nitric oxide / Histone deacetvlase / Brain-derived neurotrophic factor / Heme oxygenase |
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| Research Abstract |
This study addressed the mechanisms of microglia-mediated dopaminergic neurodegeneration as well as the effects of neuroprotective drugs expected to have novel pharmacodynamic actions. (1) Am80, a retinoid RAR agonist, inhibited dopaminergic neuron death induced by IFN- γ/LPS. Am80 increased the expression of BDNF mRNA in cultured midbrain tissues, and the protective effect of Am80 was reversed by a TrkB inhibitor and anti-BDNF neutralizing antibodies. BDNF, whose production is enhanced by RAR stimulation, is suggested to protect dopaminergic neurons in an autocrine / paracrine manner. (2) Resveratrol, an activator of sirtuin family of histone deacetylases, prevented dopaminergic neuron death induced by MPP+ and thrombin. However, the inhibitor of histone deacetylases did not affect the protective action of resveratrol. Resveratrol prevented the increase in the production of reactive oxygen species and the depletion of glutathione induced by MPP+, suggesting that antioxidative properties are involved in the protective effect of resveratrol. On the other hand, dopaminergic neuron death and enhanced p53 acetylation induced by DNA alkylating agents were inhibited by resveratrol and NAD, indicating that sirtuin-activating properties may be involved in neuroprotection under several circumstances. (3) IFN- γ/LPS, NO donors and a cyclic GMP analog all induced HO-1 expression in cultured midbrain tissues. HO-1 induction in dopaminergic neurons in response to IFN- γ/LPS was suppressed by a soluble guanylate cyclase (sGC) inhibitor. An HO-1 inhibitor and a sGC inhibitor exacerbated, whereas an HO-1 activator and a cyclic GMP analog prevented, dopaminergic neuron death induced by IFN-γ/LPS. The results suggest that induction of HO-1 expression via NO-cyclic GMP signaling pathway functions as an endogenous protective mechanism of dopaminergic neurons.
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[Journal Article] Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo2007
Author(s)
Fujimoto, S., Katsuki, H., Ohnishi, M., Takagi, M., Kume, T., Akaike, A
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Journal Title
Neuroscience. 144(2)
Pages: 694-701
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults2007
Author(s)
Okawara, M., Katsuki, H., Kurimoto, E., Shibata, H., Kume, T., Akaike, A
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Journal Title
Biochem Pharmacol. 73(4)
Pages: 550-560
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Proteasome inhibition induces glutathione synthesis and protects cells from oxidative stress : relevance to Parkinson disease2007
Author(s)
Yamamoto, N., Sawada, H., Izumi, Y., Kume, T., Katsuki, H., Shimohama, S., Akaike, A
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Journal Title
J Biol Chem. 282(7)
Pages: 4364-4372
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity2007
Author(s)
Izumi, Y., Sawada, H., Yamamoto, N., Kume, T., Katsuki, H., Shimohama, S., Akaike, A
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Journal Title
Eur J Pharmacol. 557(2-3)
Pages: 132-140
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury2007
Author(s)
Ohnishi, M., Katsuki, H., Fujimoto, S., Takagi, M., Kume, T., Akaike, A
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Journal Title
Exp Neurol. 206(1)
Pages: 43-52
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Donepezil potentiates nerve growth factor-induced neurite outgrowth in PC12 cells2007
Author(s)
Oda, T., Kume, T., Katsuki, H., Niidome, T., Sugimoto, H., Akaike, A
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Journal Title
J Pharmacol Sci. 104(4)
Pages: 349-354
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Plasminogen potentiates thrombin cytotoxicity and contributes to pathology of intracerebral hemorrhage in rats2007
Author(s)
Fujimoto, S., Katsuki, H., Ohnishi, M., Takagi, M., Kume, T., Akaike, A
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Journal Title
J Cereb Blood Flow Metab. 28(3)
Pages: 506-515
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Regulation of intracellular dopamine levels by dopaminergic drug involvement of vesicular monoamine transporter2007
Author(s)
Izumi, Y., Yamamoto, N., Kume, T., Katsuki, H., Sawada, H., Akaike, A
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Journal Title
Eur J Pharmacol. 582(1-3)
Pages: 52-61
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Glycyrrhizin inhibits interIeukin-8 production and nuclear factor-κB activity in lung epithelial cells, but not through glucocorticoid receptors2007
Author(s)
Takei, H., Baba, Y., Hisatsune, A., Katsuki, H., Miyata, T., Yokomizo, K., Isohama, Y
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Journal Title
J Pharmacol Sci. 106(3)
Pages: 460-468
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A critical role of TRPM2 in neuronal cell death by hydrogen peroxide2006
Author(s)
Kaneko, S., Kawakami, S., Hara, Y., Wakamori, M., Itoh, E., Minami, T., Takada, Y., Kume, T., Katsuki, H., Mori, Y., Akaike, A
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Journal Title
J Pharmacol Sci. 101(1)
Pages: 66-76
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Serofendic acid, a neuroprotective substance derived from fetal calf serum, inhibits mitochondrial membrane depolarization and caspase-3 activation2006
Author(s)
Kume, T., Taguchi, R., Katsuki, H., Akao, M., Sugimoto, H., Kaneko, S., Akaike, A
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Journal Title
Eur J Pharmacol. 542(1-3)
Pages: 69-76
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade2006
Author(s)
Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Sugimoto, H., Akaike, A
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Journal Title
Neuropharmacology. 51(3)
Pages: 474-486
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Contribution of endogenous glycine site NMDA agonists to excitotoxic retinal damage in vivo2006
Author(s)
Hama, Y., Katsuki, H., Tochikawa, Y., Suminaka, C., Kume, T., Akaike, A
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Journal Title
Neurosci Res. 56(3)
Pages: 279-285
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Neuroprotective effects of galanthamine and tacrine against glutamate neurotoxicity2006
Author(s)
Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Niidome, T., Sugimoto, H., Fujii, T., Okabe, S., Akaike, A
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Journal Title
Eur J Pharmacol. 549(1-3)
Pages: 19-26
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Involvement of polyamines in hemorrhagic brain injury2008
Author(s)
Takagi, M., Katsuki, H., Fujimoto, S., Ohnishi, M., Kume, T., Akaike, A
Organizer
The 128th Annual Meeting of the Pharmaceutical Society of Japan
Place of Presentation
Yokohama
Year and Date
2008-03-28
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Involvement of endogenous dopamine in dopaminergic neuronal death induced by glutamate2007
Author(s)
Izumi, Y., Sawada, H., Yamamoto, N., Kume, T., Katsuki, H., Akaike, A
Organizer
The 30th Annual Meeting of the Japan Neuroscience Society
Place of Presentation
Yokohama
Year and Date
2007-09-11
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Study on the mechanisms of the enhanced sensitivity to the neuroprotective effect of donepezil via nicotinic receptor up-regulation2007
Author(s)
Takada-Takatori, Y., Kume, T., Katsuki, H., Niidome, T., Sugimoto, H., Fujii, T., Okabe, S., Akaike, A
Organizer
The 127th Annual Meeting of the Pharmaceutical Society of Japan
Place of Presentation
Toyama
Year and Date
2007-03-30
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Mechanisms of the nicotinic receptor up-regulation induced by chronic treatment with donepezil and sensitization to donepezil-induced neuroprotection2007
Author(s)
Takada-Takatori, Y., Kume, T., Katsuki, H., Niidome, T., Sugimoto, H., Fujii, T., Okabe, S., Akaike, A
Organizer
The 80th Annual Meeting of the Japanese Pharmacological Society
Place of Presentation
Nagoya
Year and Date
2007-03-15
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Multiple mechanisms behind the antiparkinsonian activity of(-)-1-(Benzofuran-2-y1)-2-propylaminopentane2006
Author(s)
Takahata, K., Tsunekawa, H., Hirami, C., Yoshimi, K., Shimazu, S., Yoneda, F., Katsuki, H., Akaike, A
Organizer
The 29th Annual Meeting of the Japan Neuroscience Society
Place of Presentation
Kyoto
Year and Date
2006-07-19
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of neuron death by endogenous ligands of the glycine-binding site of NMDA receptors in cerebrocortical slice cultures2006
Author(s)
Watanabe, Y., Katsuki, H., Nonaka, M., Fujimoto, S., Kume, T., Akaike, A
Organizer
The 109th Kinki Regional Meeting of the Japanese Pharmacological Society
Place of Presentation
Kurashiki
Year and Date
2006-06-16
Description
「研究成果報告書概要(欧文)」より
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