PPARα转基因小鼠在药物评价中的应用研究

Application of PPARα transgenic mice in drug evaluation

目的研究过氧化物酶体增殖激活受体α激动剂药物在PPARα转基因小鼠体内对肝肾功能、血脂指标的影响,以评价该模型能否能应用于药效学研究中。方法选择27只6周龄的PPARα小鼠给予高脂饲料喂养一个月,随机分成3组,9只/组,分别为对照组1,高剂量组(非诺贝特60 mg/kg)和低剂量组(30 mg/kg)。同时选择9只C57BL/6小鼠作为对照组2。连续灌胃一个月,在动物给药前后分别检测肝功能指标、肾功能指标和血脂指标,并观察动物的一般生长情况。结果①给药后各组比较:与对照组1比较,非诺贝特各剂量组在PPARα转基因小鼠体内均能明显升高血脂中CHO和HDL-C(P<0.05),明显降低TG(P<0.05)。各组之间的体重没有明显的差异(P>0.05)。②给药前后比较:与给药前比较,给药后高剂量组能明显降低ALT、AST、ALP、BUN、TG(P<0.05);能明显升高CHO、HDL-C(P<0.01)。而低剂量组能明显降低ALP(P<0.05);能明显升高CHO、HDL-C(P<0.05)。结论 PPARα转基因小鼠评价PPARα激动剂药物比常规C57BL/6小鼠更敏感,是一个新的动物模型。

Objective To research the impact of PPARα agonist on liver and kidney function and blood fat index in PPARα transgenic mouse, and to detect these indices in the model if they can be applied to the study of pharmacodynamics. Methods Twenty-seven mice, at the age of 6 weeks, were divided into three group （ each n = 9）, and fed with high-fat forage for a mounth. They were control group one, high dose group（60 mg/kg of fenofibrate） , low dose group（30 mg/kg of fenofibrate）. At the same time, 9 C57BL/6 mice were set as the control group two. The time of gavage administration lasted one month. The liver function index, kidney function index , and blood fat index Were tested before and after the drug administration. The growth of the mice was also observed. Results （1）The comparison after fenofibrate administration ：Compared with control group one, in the PPARα transgenie mouse with the fenofibrate dosage of 60 mg/kg, 30 mg/kg, the level of triglycerides （TG） was reduced markedly （P 〈 0. 05 ）and the high-density lipoprotein cholesterol （HDL-C） ,CHO level was increased markedly （P 〈 0.05）. However, there was no obvious statistics difference on weigh among all groups（P 〉 0.05）. （2）The comparison before and after fenofibrate administration ：Compared with the value before fenofibrate administration, the ALT.AST.ALP.BUN.TG were obviously reduced after the administration of 60 mg/ kg fenofibrate （P 〈 0. 05） ,in addition, the CHO.HDL-C were obviously raised （P 〈 0.01 ）. However, in the 30 mg/kg fenofibrate administration group, ALP was obviously reduced （P 〈 0. 05） ,and the CHO.HDL-C were obviously raised （P 〈 0. 05）. Conclusion Compared with C57BL/6 mouse ,the PPARα transgenic mouse has the sensibility in evaluation of PPARα agonist. It is a new animal model.