1997 Fiscal Year Final Research Report Summary
Development of a novel drug for treatment of rhematoid Arthritis based on tyrosine kinase inhibition
| Project/Area Number |
08557136
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
医薬分子機能学
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| Research Institution | The University of Tokushima |
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Principal Investigator |
TAKAISHI Yoshihisa The University of Tokushima, Fac.Pharmaceut.Sci., Pharmcognosy, Professor, 薬学部, 教授 (60035558)
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| Co-Investigator(Kenkyū-buntansha) |
ONO Yoshihisa Otsuka Pharmaceut.Co., Institute of Cell Technology, Head researcher, 細胞工学研究所, 研究員
TAKIGUCHI Yoshiharu The University of Tokushima, Fac.Pharmaceut.Sci., Clinical Pharmcology, Associat, 薬学部, 助教授 (40163349)
HISAYAMA Tetsuhiro The University of Tokushima, Fac.Pharmaceut.Sci., Pharmcology, Associate Prof., 薬学部, 助教授 (70130383)
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| Project Period (FY) |
1996 – 1997
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| Keywords | Vascular smooth muscle / Rheumatoid arthritis / Trip toquinone / Nitric oxide / Enzyme induction / Calcium / Endothelium / Tyrosine kinase |
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| Research Abstract |
Triptegrium wilfordii var regelli has been used as a traditional Chinese medicine for rheumatoid arthritis. The therapeutic effectiveness of Triptergium wilfordii in a variety of autoimmune diseases including rheumatoid arthritis has been attributed to its immunosuppressive action. Trip toquinone A (TQA) is a principal component of Triptergium wilfordii with a quinoid type diterpene structure. We investigated the effects of TQA on expression of inducible nitric oxide synthase (iNOS) in vascular smooth muscle and on, Ca-mobilization for activation of constitutive type nitric oxide synthase (cNOS) in endothelial cells. TQA inhibited initiation of arginine-induced relaxation, nitrite accumulation, cyclic GMP production and iNOS mRNA transcription primed by LPS- or interleukin-1 in rat aortic muscular strips. These results suggest that TQA prevented expression of the iNOS gene by inflammatory stimuli in vascular smooth muscle cells. On the other hand, TQA inhibited endothelium-dependent cyclopiazonic acid-induced relaxation, but not a relaxation by A23187 or nitroprusside. These pharmacological profiles of TQA were shared by the tyrosine kinase inhibitor herbimycin A with the same structure moiety as TQA.TQA prevented autophosphorylation of tyrosine residues of EGF receptors in A431 cells. Taken together, we propose that TQA is a unique antiinflammatory drug with an inhibitory effect on tyrosine kinase to be involved in induction of iNOS.
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[Publications] Moritoki, H., Hisayama, T., Kida, K., Kondoh, W., Inoue, S.& Takaishi, Y.: "Inhibition by triptoquinone-A of LPS- and IL-1beta-primed induction of NO synthase in rat thoracic aorta" Life Sci.59. PL49-54 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Niwa, M., Tsutsumishita, Y., Kawai, Y., Takahata, H., Nakamura, H., Futaki, S., Takaishi, Y., Kondoh, W.& Moritoki: "Suppression of inducible nitric oxide synthase mRNA expression by triptoquinone A" biochem.Biophys.Res.Commun.224. 579-585 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Mori, K., Takeuchi, S., Moritoki, H., Tsuchiya, K., Nakaya, Y., Matsuoka, S.& Kuroda, Y.: "Endothelium-dependent relaxation of rat thoracic aorta by amrinone-induced nitric oxide release" Eur.Heart.J.17. 308-316 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Moritoki, H., Hisayama, T., Takeuchi, S., Kondoh, W., Inoue, S.& Kida, K.: "Inhibition by SK &F96365 of NO-mediated relaxation induced by Ca^<2+>-ATPase inhibitors in rat thoracic aorta" Br.J.Pharmacol.117. 1554-1548 (1996)
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