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目的:用培美曲塞(pemetrexed,PMX)建立叶酸缺乏的神经管畸形(neural tube defect,NTD)动物模型,并探讨其对神经上皮细胞增殖和凋亡的影响。方法:应用不同剂量PMX(5、10、15、17.5、20和30 mg/kg)对C57BL/6孕鼠进行干预,筛选最佳造模剂量。采用磷酸化组蛋白H3(pH3免疫组化的方法以及TUNEL方法)观察胎鼠神经上皮增殖和凋亡情况。结果:随着PMX剂量的增加,小鼠胚胎的吸收胎和畸形率逐渐增加,其中17.5mg/kg体重组的NTD的发生率最高(30.6%),被筛选为最佳造模剂量。pH3免疫组化和TUNEL结果显示,与正常对照组相比,NTD小鼠胚胎神经上皮细胞增殖减少(P<0.05),凋亡增加(P<0.05)。结论:PMX能诱导NTD的发生,其机制可能是因为PMX阻断了叶酸代谢通路并导致神经上皮细胞的增殖抑制和过度凋亡。
OBJECTIVE: To establish an animal model of folic acid deficiency by neural tube defect (NTD) using pemetrexed (PMX) and investigate its effect on the proliferation and apoptosis of neural epithelial cells. Methods: Different doses of PMX (5, 10, 15, 17.5, 20 and 30 mg / kg) were used to intervene C57BL / 6 pregnant rats to screen the best model dose. The phosphorylation of histone H3 (pH3 immunohistochemical method and TUNEL method) was used to observe the proliferation and apoptosis of fetal rat neural epithelium. Results: With the increase of PMX dose, the fetus fetus and deformity rate gradually increased. The incidence of NTD was the highest (30.6%) in 17.5mg / kg body weight group, which was screened as the best model dose. The results of immunohistochemistry and TUNEL at pH3 showed that compared with the normal control group, the proliferation of NTD mouse embryos neuroepithelial cells was decreased (P <0.05) and the apoptosis was increased (P <0.05). CONCLUSION: PMX can induce the development of NTD. The possible mechanism is that PMX blocks the folate metabolic pathway and leads to the inhibition of proliferation and excessive apoptosis of neuroepithelial cells.