title: Norisoboldine, an alkaloid compound isolated from Radix Linderae, inhibits synovial angiogenesis in adjuvant-induced arthritis rats by moderating Notch1 pathway-related endothelial tip cell phenotype.
abstract: Synovial angiogenesis is well recognized as participating in the pathogenesis of rheumatoid arthritis (RA) and has been regarded as a potential target for RA therapy. Previously, we have shown that norisoboldine (NOR) can protect joints from destruction in mice with collagen II-induced arthritis (CIA). Here, we investigate the effect of NOR on synovial angiogenesis in adjuvant-induced arthritis (AA) rats, and clarify the mechanisms in vitro. NOR, administered orally, significantly reduced the number of blood vessels and expression of growth factors in the synovium of AA rats. In vitro, it markedly prevented the migration and sprouting of endothelial cells. Notably, the endothelial tip cell phenotype, which is essential for the migration of endothelial cells and subsequent angiogenesis, was significantly inhibited by NOR. This inhibitory effect was attenuated by pretreatment with N-{N-[2-(3,5-difluorophenyl) acetyl]-(S)-alanyl}-(S)-phenylglycine tert-butyl ester, a Notch1 inhibitor, suggesting that the action of NOR was related to the Notch1 pathway. A molecular docking study further confirmed that NOR was able to promote Notch1 activation by binding the Notch1 transcription complex. In conclusion, NOR was able to prevent synovial angiogenesis in AA rats, which is a putatively new mechanism responsible for its anti-rheumatoid effect. The anti-angiogenesis action of NOR was likely achieved by moderating the Notch1 pathway-related endothelial tip cell phenotype with a potential action target of the Notch1 transcription complex.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, State Key Laboratory of Natural Medicines.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lu
authors.forename: Shuai
authors.initials: S
authors.lastname: Lu
authors.forename: Xinghua
authors.initials: X
authors.lastname: Gao
authors.forename: Yubin
authors.initials: Y
authors.lastname: Luo
authors.forename: Bei
authors.initials: B
authors.lastname: Tong
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wei
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xia
authors.forename: Guixin
authors.initials: G
authors.lastname: Chou
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001168:Arthritis / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000378:metabolism*; D013582:Synovial Fluid / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D000893:Anti-Inflammatory Agents; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; C464745:norisoboldine