| Project/Area Number |
10660104
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Bioproduction chemistry/Bioorganic chemistry
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
SHIN-YA Kazuo The University of Tokyo Institute of Molecular and Cellular Biosciences, Assistant Professor, 分子細胞生物学研究所, 助手 (20251481)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
|
|---|
| Keywords | kaitocephalin / brain ischemia / kainate / AMPA / NMDA / hippocampus / slice culture / CaィイD12+ィエD1 influx / 脳虚血疾患 / グルタミン酸毒性 / ラット海馬神経細胞 |
|---|
| Research Abstract |
In the course of our screening program for AMPA/kainate antagonists to treat brain ischemia injury known as stroke, we isolated a potent AMPA anatagonist designated kaitocephalin from a fungi identified to Eupenicillium shearii. This compound effectively protected rat hippocampal neurons from AMPA and kainate toxicity without showing cytotoxicity. Since the stereochemistry plays a significant role in the biological activities on glutamate receptor, we established the absolute stereochemistry of kaitocephalin as 2S3S4R7R9S by analyzing the NMR spectra such as NOEs applying to the chemically modified compounds.
In the receptor binding assay for glutamate agonists, kaitocephalin showed potent binding activity to the agonist binding site of NMDA receptor. It also exhibited binding affinities AMPA receptor but showed slight binding activity on kainate receptor. In this way it has a high affinity to NMDA receptor, we investigated the protective effect of kaitocephalin against NMDA toxicity in
… More
rat hippocampal neurons. It effectively protected rat hippocampal neurons from neuronal damage induced by NMDA. To reveal the mode of action, we next studied the inhibitory effects of kaitocephalin on CaィイD12+ィエD1 influx induced by glutamate agonists. Kaitocephalin blocked CaィイD12+ィエD1 influx induced by AMPA but not by kainate in rat hippocampal neurons. This result is coincident to affinity binding experiments, but quite different from the hypothesis of CaィイD12+ィエD1 induced neurotoxicity. So that we employed rat hippocampal organotypic culture system using rat hippocampal slices in which the selective response to the different glutamate agonists could be observed. Kaitocephalin protected CA1 and CA3 regions from NMDA, AMPA and kainate. Kaitocephalin blocked CaィイD12+ィエD1 influx in CA1 and CA3 region elicited by NMDA and AMPA, respectively. To the contrary, kaitocephalin failed to block CaィイD12+ィエD1 influx mediated through kainate receptor. These results proved that CaィイD12+ィエD1 influx induced by glutamate agonists did not always attribute neuronal cell death. It is a quite important disovery in the central nervous physiology and also imply the novel hypothesis to the mechanism of neuronal cell death. Less
|
