普乐可复对大鼠脑内兴奋性氨基酸和氧自由基的影响

Effect of Prograf on Excitatory Amino Acids and Free Radicals in Rats' Brains

目的 观察应用普乐可复后引起大鼠的神经毒性症状,大鼠脑组织氧自由基和兴奋性氨基酸的改变,探讨其与普乐可复血药浓度的关系。方法 雄性SD大鼠36只,随机分为3组:口服普乐可复5、10 mg·kg-1·d-1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;实验结束时检测不同部位脑组织SOD、MDA和EAAs含量的变化。结果 口服普乐可复10 mg·kg-1·d-1组大鼠出现了易激惹和轻度震颤的症状;脑内EAAs和MDA水平的增高以及SOD水平的下降。血药稳态浓度从19.4至90.4 ng·mL-1不等,平均(46.17±23.07)ng·mL-1,与5 mg·kg-1·d-1组大鼠相比[(8.6±3.2)ng·mL-1]有显著差异;大鼠出现神经毒性症状的最低血药浓度为25.6 ng·mL-1;5 mg·kg-1·d-1组大鼠未发现神经毒性症状;脑内EAAs、MDA和SOD水平也无明显变化。结论 应用普乐可复后大鼠出现神经毒性症状的最低稳态血药浓度为25.6 ng·mL-1,当稳态血药浓度在5～20 ng·mL-1范围内时,较为安全。大鼠海马、基底节处SOD、MDA、EAAs含量的变化与神经毒性症状密切相关。

Purpose: To observe the neurotoxicity of Prograf(FK506) in rats and investigate the change of excitatory amino acids and free radicals in the rats' brains. To provide some effective strategy to treat the neurotoxic syptoms results from using the immunosuppressant Prograf after organt transplantation. Methods: Thirty six male SD rats were randomly assigned to three groups (n = 12):(1) 10 mg&middotkg-1&middotd-1Prograf group; (2) 5 mg&middot kg-1&middotd-1 Progrf group; (3) control (untreated) group. The neurotoxic syptom of rats were regularly observed; The plasma concentrations of Prograf were measured twice a week; the EAAs, SOD and MDA were determined at the end of the study. Results: The different degrees of irritability and tremors were found in 10 mg&middotkg-1&middot d-1 Prograf group. The plasma concentrations of Prograf in this group were ranged from 19.4 ng&middotmL-1 to 90.4 ng&middotmL -1 and there were significant difference compared to the 5 mg&middotkg-1&middotd-1 group [(8.6 ± 3.2) ng&middotmL-1], (P -1 could be consided safety relatively. The change of the level of EAAs, SOD and MDA in hippocampus and basipodite may be the mechanisms of the neurotoxicity resulted from Prograf.