| Project/Area Number |
10557021
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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 | 展開研究 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
TANABE Tadashi National Cardiovascular Center Research Institute Department of Pharmacology, Director, 薬理部, 部長 (60025624)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMONISHI Manabu National Cardiovascular Center Research Institute Department of Pharmacology, Research Staff, 薬理部, 室員 (70300978)
YOKOYAMA Chieko National Cardiovascular Center Research Institute Department of Pharmacology, Section Chief, 薬理部, 室長 (90200914)
INOUE Hiroyasu National Cardiovascular Center Research Institute Department of Pharmacology, Section Chief, 薬理部, 室長 (40183743)
ASHIDA Yasuko Takeda Chemical Industries, Pharmaceutical Division, Director, 創薬研究本部, 室長
MURAKAMI Makoto Showa University, Faculty of Pharmaceutical Sciences, Department of Health Chemistry, Associate Professor, 薬学部, 助教授 (60276607)
MUROTA Sei-itsu Tokyo Medical and Dental University Graduate School, Department of Physiological Chemistry, Professor, 大学院, 教授 (50072989)
YAMAMOTO Kei The University of Tokushima School of Medicine, Department of Biochemistry, Research Associate, 医学部, 助手 (30304504)
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| Project Period (FY) |
1998 – 1999
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| Keywords | cyclooxygenase / Isozyme / cycloxygenase-2 / arachidonic acid / phospholipase AィイD22ィエD2 / inflammation / prostaglandins / inhibitor |
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| Research Abstract |
Non-steroidal drugs including aspirin inhibit the synthesis of inflammatory prostaglandins (PG) by inhibiting cyclooxygenases (COX). We investigated the mechanisms of the inhibition of two known COX isozymes by non-steriodal and steroidal anti-inflammatory drugs and natural compounds for the development of new anti-inflammatory drugs without gastrointestinal side effects, and obtained the following results. (1) The expression of COX-2 gene by LPS and TPA was inhibited by steroidal inflammatory reagent, dexamethazone and 15d-PGJィイD22ィエD2 and the degree of inhibition of COX-2 depended on the levels of their receptors. (2) Endogeneous inhibitor of COX induced by serum was found in cytosolic faction of cells with the NIH3T3 expressing either COX-1 or COX-2 only. (3) COX-2 was found to be inhibited by natural occurring polyphenol compounds, rasveratrol, caffeic acid phenethylester and humulon, and the mechanisms of the inhibition were studied. (4) An inhibitor found showed equal inhibitions of COX-1 and COX-2 without gastrointestinal side effects. (5) COX-2 in a mouse osteoblastic cell MC3T3-E1 was induced by various PGs produced by own cells, and a marked induction of PGIィイD22ィエD2 receptor was induced by TNFα. (6) We have examined functional coupling between phospholipase AィイD22ィエD2 (PLAィイD22ィエD2) and COX isozymes in the immediate and delayed PG-biosynthetic responses using various cell lines. Of the (PLAィイD22ィエD2 isozymes to date, cytosolic (PLAィイD22ィエD2 an several secretory (PLAィイD22ィエD2 isozymes (IIA, IID, V and X) are capable of supplying arachidonic acid to both COX-1 and -2 in the immediate response and predominantly to COX-2 in the delayed response.
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