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Development of a novel drug for treatment of rhematoid Arthritis based on tyrosine kinase inhibition

基于酪氨酸激酶抑制的治疗类风湿性关节炎新药的开发

基本信息

批准号：
08557136
负责人：
TAKAISHI Yoshihisa
金额：
$ 8万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08557136/
关键词：
Vascular smooth muscle Rheumatoid arthritis Trip toquinone Nitric oxide Enzyme induction Calcium Endothelium Tyrosine kinase メッセンジャーRNA

项目摘要

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.

雷公藤是治疗类风湿性关节炎的传统中药。雷公藤在包括类风湿性关节炎在内的多种自身免疫性疾病中的治疗效果归因于其免疫抑制作用。雷公藤甲素（Trip to quinone A，TQA）是雷公藤的主要成分，具有醌型二萜结构.我们研究了TQA对血管平滑肌诱导型一氧化氮合酶（iNOS）表达和对内皮细胞组成型一氧化氮合酶（cNOS）激活的Ca动员的影响。TQA抑制了大鼠主动脉肌条中由LPS或白细胞介素-1引发的精氨酸诱导的舒张、亚硝酸盐积累、cGMP产生和iNOS mRNA转录的启动。这些结果表明，TQA阻止血管平滑肌细胞中的炎症刺激的iNOS基因的表达。另一方面，TQA抑制内皮依赖性cyclopiazonic酸诱导的舒张，但不松弛A23187或硝普钠。酪氨酸激酶抑制剂除莠霉素A与TQA具有相同的药理作用，TQA可抑制A431细胞EGF受体酪氨酸残基的自磷酸化。综上所述，我们认为TQA是一种独特的抗肿瘤药物，对参与诱导iNOS的酪氨酸激酶具有抑制作用。