摘要
目的建立一种新的急性高尿酸血症小鼠模型并利用该模型对PNP酶抑制剂Ulodesine进行体内药效作用评价。方法小鼠腹腔注射肌苷(inosine)和皮下注射氧嗪酸钾(oteracil potassium)诱导体内尿酸蓄积,在一定时间段内对小鼠进行内眦静脉或摘眼球采血,测定血清尿酸值,判断小鼠急性高尿酸血症模型成功与否;再利用酶动力学分析Ulodesine对PNP酶的体外抑制作用,并于造模前给予小鼠灌胃Ulodesine,造模后测定血清尿酸值,评价Ulodesine的降血尿酸作用。结果小鼠腹腔注射200 mg·kg^(-1)肌苷联合皮下注射200 mg·kg^(-1)氧嗪酸钾在1.5 h时能形成较为稳定的急性高尿酸血症;酶动力学测定结果显示Ulodesine对PNP酶有极强的抑制作用,其IC_(50)值为2.293 nmol·L^(-1);另外,Ulodesine的体内药效表明,Ulodesine能够明显减低急性高尿酸血症小鼠体内尿酸水平。结论我们已经成功地建立了一种新的急性高尿酸血症小鼠模型,该造模制作方法更简单有效,且该模型可以应用于验证PNP酶抑制剂。
Aim To establish a novel acute hyperuricemia mouse model and apply it to evaluate the hyporucicemia effects of Ulodesine,a purine nucleoside phosphorylase( PNP) inhibitor. Methods The mice were intraperitoneal injected inosine and subcutaneous injected Oteracil potassium to induce accumulation of uric acid,and the animal blood was collected from eyeball or vena angularis in different time points. The levels of serum uric acid were measured and determined to test whether the acute hyperuricemia mouse model were successful or not. In order to verify the hyperuricemia seen in the model was associated with the accumulation of inosine,which was converted to uric acid by action of PNP,hyporucicemia effects of Ulodesine,a PNP inhibitor,was assessed in an enzyme assay and confirmed by using the newly established model. Result Accumulation of uric acid in the blood of mouse modelswas observed by combined injections of intraperitoneal200 mg · kg^(-1)inosine and subcutaneous 200 mg ·kg^(-1)Oteracil potassium respectively after 1. 5 h. The enzyme assay indicated that Ulodesine was a potently PNP inhibitor with IC_(50 )of 2. 293 nmol·L^(-1). IV injection of Ulodesine eliminated uric acid accumulations in blood of the mouse model,which was expected as the in vivo action of Ulodesine. Conclusions A novel acute hyperuricemia mouse model is established. This is a relatively easy and more effective protocol to generate the hyperuricemia in mice,which will be a useful platform to assess the anti-hyperuricemia activity of PNPtarget drugs in vivo.
出处
《中国药理学通报》
CAS
CSCD
北大核心
2017年第6期883-886,共4页
Chinese Pharmacological Bulletin
基金
云南省科技厅高层次科技创新人才计划(No 2013HA018)
