2004 Fiscal Year Final Research Report Summary
Brain dysfunction induced by tyrosine nitrosylation of synaptic protein
| Project/Area Number |
14370031
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Nagoya University |
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Principal Investigator |
NABESHIMA Toshitaka Nagoya University, University Hospital, Professor, 医学部附属病院, 教授 (70076751)
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| Co-Investigator(Kenkyū-buntansha) |
NTTTA Atsumi Nagoya University, University Hospital, Associate Professor, 医学部附属病院, 助教授 (20275093)
YAMADA Kiyofumi Kanazawa University, Graduate School of Natural Science and Technology, Professor, 大学院・自然科学研究科, 教授 (30303639)
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| Project Period (FY) |
2002 – 2004
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| Keywords | amyloid β protein / alzheimer's disease / nitric oxide / inducible nitric oxide synthase / tyrosine nitration / synaptophysin / inteiieikin-1β / turner necrosis factor |
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| Research Abstract |
We have investigated the mechanisms of brain dysfunction induced by amyloid β(Aβ) in relation to inducible nitric oxide(NO) synthase (iNOS), oxidative stress, intracellular signaling and neurotransmitter receptors. Continuous infusion of Aβ into the cerebroventricle in rats resulted in the expression of iNOS, overproduction of NO and tyrosine nitration of synaptophysin in the hippocampus. The iNOS inhibitors and peroxynitrite scavengers prevented the Aβ-induced impairment of memory and nicotine-evoked acetylcholine(ACh) release in the hippocampus. Aβ infusion also resulted in a significant reduction of antioxidant substances such as glutathione. These findings suggest a role for oxidative stress in Aβ-induced brain dysfunction. Furthermore, chronic infusion of Aβ decreased the activity of protein kinase C in the hippocampus and abolished the translocation induced by phorbol-dibutyrate. Regarding the functional alterations of neurotransmitter receptors induced by Aβ, we focused on the role of α7 nicotinic ACh receptors(nAChR) and N-methyl-D-aspartate receptors(NMDAR). By using a real-time optical recording technique, we found an impairment of the basal synaptic transmission and long-term potentiation(LTP) at the Schaffer collateral-CA1 synapse in the hippocampal slices from Aβ-infused rats. Chronic Aβ infusion attenuated the responsibility to the α7 nAChR agonist while the blockade of the receptors with selective antagonists led to the deficit in the hippocampal LTP in control animals. Pretreatment with α7 nAChR agonist of the slices from Aβ-infused rats reversed the deficit in LTP. These results suggest that dysfunction of α7 nAChR plays a crucial role in Aβ-induced impairment of LTP in the hippocampus. Lastly, we found that memantine, a low affinity NMDAR antagonist, prevented the development of short-term memory deficit in Aβ-treated rats. It is suggested that both α7 nAChR and NMDAR could be important targets for drug development in Alzheimer's disease.
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Research Products
(106 results)
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[Journal Article] Role of tumor necrosis factoi-α in methamphetamine-induced drug dependence and neurotoxicity.2004
Author(s)
Nakajima A, Yamada K, Nagai T, Uchiyama T, Miyamoto Y, Mamiya T, He J, Nitta A, Mizuno M, Tran M.H, Seto A, Yoshimura M, Kitaichi K, Hasegawa T, Saito K, Yamada Y, Seishima M, Sekikawa K, Kim H.C, Nabeshima T.
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Journal Title
J Neurosci. 24
Pages: 2212-2225
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor(GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kB transcription factor.2004
Author(s)
Maruyama W, Nitta A, Shamoto-Nagai M, Hirata Y, Akao Y, Yodim M, Furukawa S, Nabeshima T, Naoi M.
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Journal Title
Neurochem Int. 44
Pages: 393-400
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] α7-type nicotine acetylcholine receptor and prodynorphin mRNA expression after administration of (-)-nicotine and U-50, 488H in β-amyloid peptide (25-35)-treated mice2004
Author(s)
Hiramatsu, M., Watanabe, M., Baba, S., Kojima, R., Nabeshima, T.
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Journal Title
Current Status of Drug Dependence/Abuse Studies(Ed.by Ali SF, Nabeshima T.and Yanagita T.)Ann.N.Y.Acad.Sci. 1025
Pages: 508-514
Description
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[Journal Article] Immunocytochemical evidence that amyloid β(1-42) impairs endogenous antioxidant systems in vivo.2003
Author(s)
Kim H.-C, Yamada K, Nitta A, Olariu A, Tran M.H, Mizuno M, Nakajima A, Nagai T, Kamei H, Jhoo W.-K, Im D.-H, Shin E.-J, Hjelle O.P, Ottersen O.P, Park S.C, Kato K, Mirault M.-E, Nabeshima, T.
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Journal Title
Neuroscience 119
Pages: 399-419
Description
「研究成果報告書概要(欧文)」より
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