Studies on substances of microbial origin which protect central nervous system

the course of our screening program for AMPA/kainate antagonists to treat brain ischemia injuryknown as stroke，我们isolated a potent AMPA anatagonist designated kaitocephalin from a fungi identified toEupenicillium shearii. This compound effectively protected rat hippocampal neurons from AMPA andkainate toxicity without showing cytotoxicity.自从stereochemistry plays a significant role inthe biological activities on glutamate receptorwe established the absolute stereochemistry of kaitocephalin as 2s3s4r7r9s by analyzing the NMRspectra such as NOEs applying to the chemically modified compounds.In the receptor binding assay forglutamate agonists,kaitocephalin showed potent binding activity to the agonist binding site of NMDA receptor. It alsoexhibited binding affinities AMPA receptor，但showed slight binding activity on kainate receptor。In this way it has a high affinity to NMDA receptor我们投资于kaitocephalin against NMDA toxicity in…rat hippocampal neurons. It effectively protected rat hippocampal neurons from neuronaldamage induced by NMDA. To reveal the mode of actionwe next studied the inhibitory effects of kaitocephalin on Ca D12+ glutamate influx induced by glutamateagonists. Kaitocephalin blocked Ca D12+ D12 influx induced by AMPA but not by kainate in rathippocampal neurons.这个结果是coincident to affinity binding experiments，but quite different from the hypothesis of Ca D12+ D1 induced neurotoxicity.所以我们经营rat hippocampal organotypic文化系统使用rat hippocampal slices in which the selectiveresponse to the different glutamate agonists could be observed. Kaitocephalin protected CA1 and CA3regions from NMDA，AMPA and kainate. Kaitocephalin blocked Ca D12+ D12 influx in CA1 and CA3 region elicited by NMDAAMPA, respectively. To the contrary，kaitocephalin failed to block Ca D12+ D12 influx mediated through kainate receptor. These resultsproved that Ca D12+ D12 influx induced by glutamate agonists did not always attribute neuronal celldeath. It is a quite important disovery in the central nervous physiology and also imply the novelhypothesis to the mechanism of neuronal cell death. Less

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