| Project/Area Number |
10044328
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A).
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Biological pharmacy
|
|---|
| Research Institution | Kanazawa University (1999-2000)
Setsunan University (1998) |
|---|
Principal Investigator |
YONEDA Yukio Kanazawa University Faculty of Pharmaceutical Sciences, Department of Molecular Pharmacology, Professor, 薬学部, 教授 (50094454)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OGITA Kiyokazu Setsunan University, Faculty of Pharmaceutical Sciences, Department of Pharmacology, Lecturer, 薬学部, 講師 (90169219)
マレス パベル チェコ科学アカデミー, 生理学研究所, 所長
スタッスニー フランティ チェコ科学アカデミー, 生理学研究所, 助教授
ルカッセンス マックス モンペリエ大学, 理学部, 教授
|
|---|
| Project Period (FY) |
1998 – 2000
|
| Project Status |
Completed (Fiscal Year 2000)
|
| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2000: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 1999: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 1998: ¥4,800,000 (Direct Cost: ¥4,800,000)
|
|---|
| Keywords | Neuronal death / Neurotoxins / NMDA receptors / KA receptors / Transcription factors / CA1 and CA3 subfields / Dentate granule cells / c-Fos protein / カインシ酸レセプター / CA1野,CA3野錐体細胞 / 歯状,回顆粒細胞 / c-Fros蛋白質 / NMDA / 遊離カルシウム / 初代培養神経細胞 / 共焦点レーザー顕微鏡 / 神経毒性 / MAP-2 / GFAP / 神経変性疾患 / 〔^3H〕MK-801結合 / 二価鉄イオン / キノリン酸 / 鉄キレーター / シナプス膜 |
|---|
| Research Abstract |
The present study deals with modulation of gene transcription in the brain, in order to evaluate possible involvement of particular ionotropic receptor subtypes for L-glutamic acid in mechanisms underlying neuronal toxicity by excitotoxins. Transcription factors are nuclear proteins with high affinity for a particular core nucleotide sequence to modulate the activity of RNA polymerase II that is responsible for formation of mRNA from genomic DNA in the nucleus. The systemic administration of N-methyl-D-aspartic acid (NMDA) led to selective and drastic potentiation of DNA binding activity of the transcription factor activator protein-1 (AP1) in murine hippocampus. Frozen coronal sections were made with the aid of a cryostat, followed by punching out of the desired regions by a plastic capillary on dry ice under a binocular microscope. The potentiation was only seen in the dentate granule cells, but not in the CA1 and CA3 pyramidal cells. The potentiation in the dentate gyrus was transient with a peak at 2 h after administration and a decline within 4 h later, which occurred in a manner sensitive to antagonism by an NMDA channel blocker. Immunohistochemical analysis revealed that NMDA induced expression of both c-Jun and c-Fos proteins in the dentate gyrus, but not in the CA1 and CA3 subfields. By contrast, kainic acid (KA) induced drastic and prolonged potentiation of AP1 DNA binding in the CA1 and CA3 pyramidal layers in addition to dentate granule layers. The administration of KA but not NMDA led to marked potentiation of AP1 binding in areas neighboring but excluding pyramidal and granule layers. KA induced severe neuronal death in the CA1 and CA3 pyramidal layers without affecting dentate granular neurons. These results suggest that modulation of de novo synthesis of particular proteins may underlie mechanisms associated with neuronal cell death induced by excitotoxins.
|
