普乐可复对大鼠的神经毒性和脑细胞超微结构及凋亡的影响  

The neurotoxicity of Prograf and its influence on ultra microstructure and apoptosis of rats' brain

作　　者：陈开来[1] 崔尧元[1] 吕迁洲[2] 樊嘉[3] 

机构地区：[1]复旦大学附属中山医院神经外科,上海200032 [2]复旦大学附属中山医院药剂科,上海200032 [3]复旦大学附属中山医院肝癌研究所,上海200032

出　　处：《上海医学》2004年第5期334-336,i004,共4页Shanghai Medical Journal

摘　　要：目的　观察应用普乐可复后引起的大鼠神经毒性症状、大鼠脑组织超微结构改变和细胞凋亡的变化 ,为器官移植后应用普乐可复所导致的并发症提供临床防治依据。方法　雄性SD大鼠 36只 ,分为口服普乐可复 5、10mg·kg-1·d-1剂量组和空白对照组。定时观察大鼠的神经症状 ,测定普乐可复的血药浓度 ;实验结束时观察不同部位脑组织超微结构和脑细胞凋亡的情况。结果　普乐可复 10mg·kg-1·d-1剂量组大鼠出现易激惹和轻度震颤的症状 ,每只大鼠的血药稳态浓度为 19.4～ 90 .4ng/ml,平均为 (4 6 .2± 2 3.1)ng/ml;大鼠出现神经毒性症状的最低血药浓度为 2 5 .6ng/ml;该组大鼠海马、基底节处可见脑组织超微结构改变及细胞凋亡的现象。其余两组均未发现神经毒性症状、脑组织超微结构改变和脑细胞凋亡的现象。结论　应用普乐可复后大鼠出现神经毒性症状的最低血药浓度为 2 5 .6ng/ml,当血药浓度为 5～ 2 0ng/ml时较为安全。大鼠海马、基底节处神经细胞的变性、坏死和血脑屏障的破坏以及脑细胞凋亡是其病理基础和可能机制。Objective To observe the neurotoxicity of Prograf in rats with investigation on the ultrastructural changes and apoptosis of rats' brains and to provide some evidences for treating the neurotoxic symptoms resulted from using Prograf after organ transplantation. Methods Thirty six male Sprague Dowley rats were randomly assigned to three groups: Oral Prograf 5,10 mg·kg -1 ·d -1 groups and Blank control group. The neurotoxicity symptoms were observed at regular intervals. The ultrastructure and apoptosis in different areas of the brain at the termination of the experiment were studied; the plasma concentration of Prograf was also measured. Results Oral Prograf 10 mg·kg -1 ·d -1 group showed varying degrees of irritability and mild tremor.The plasma concentrations of Prograf of rats in this group ranged from 19.4 ng/ml to 90.4 ng/ml .The lowest plasma concentration of Prograf which led to the appearance of neurotoxic symptom was 25.6 ng/ml. Cell degeneration, necrosis and apoptosis could be seen in the neurons, neuroglial cells in hippocampus and basal ganglia. Whereas in the other two groups, there were no neurotoxic symptoms nor ultrastructural change and apoptosis. Conclusion The lowest plasma concentration of Prograf leading to neurotoxic symptoms is 25.6 ng/ml. It is safer to have plasma concentrations at 5 to 20 ng/ml. Degeneration and necrosis of neural cells and apoptosis in hippocampus and basal ganglia may be the main pathologic features and the possible mechanism of the neurotoxicity might be caused by Prograf.

关 键 词：普乐可复 大鼠 神经毒性 脑细胞 超微结构 细胞凋亡 免疫抑制剂 

分 类 号：R96[医药卫生—药理学]