JNK阻断剂CEP-11004对铝诱导的大鼠皮层神经元凋亡的保护作用  

Protective effect of JNK inhibitor CEP-11004 on the AlCl_3-induced apoptosis in cortical neurons of rat pups

作　　者：傅洪军[1] 董胜璋[1] 林忠宁[1] 胡前胜[1] 

机构地区：[1]中山大学公共卫生学院预防医学系,广东广州510080

出　　处：《中国药理学与毒理学杂志》2003年第2期106-110,共5页Chinese Journal of Pharmacology and Toxicology

摘　　要：目的　为探讨铝诱导神经元凋亡的信号传递机制及铝的神经毒性机制 ,并为防治神经退行性疾病提供线索 ,研究应激活化蛋白激酶 (又称c junN末端激酶 ,SAPK/JNK)的阻断剂CEP 110 0 4 (KT8138)对氯化铝 (AlCl3)诱导大鼠皮层神经元凋亡的保护作用。方法　SD乳大鼠大脑皮层神经元培养 ,FDA荧光染色法检测神经元存活率 ,Hoechst332 5 8核荧光染色 ,琼脂糖凝胶电泳检测细胞凋亡 ,SAPK/JNK分析试剂盒作激酶分析。结果　一定剂量的AlCl3(10～ 10 0 0 μmol·L- 1)可降低皮层神经元存活率 ,诱导大鼠皮层神经元凋亡 ,SAPK/JNK的磷酸化水平明显升高 (对照组的 4 .2倍 ,P <0 .0 1) ,SAPK/JNK被激活。但是 ,当CEP 110 0 4 (1～ 10 μmol·L- 1)预孵 6h后再加入 10 0 0 μmol·L- 1AlCl3染毒 6h ,SAPK/JNK的磷酸化水平呈剂量依赖性地降低 (分别是对照组的 2 .3,1.2和 0 .9倍 ,P <0 .0 5 ) ,CEP 110 0 4通过抑制细胞凋亡而促进皮层神经元的存活 ,对大鼠皮层神经元产生保护作用。结论　CEP 110 0 4可能通过抑制SAPK/JNK的活性 。AIM To clarify the signal transduction mechanism of apoptosis induced by AlCl 3 and the mechanism of neurotoxicity of aluminum. METHODS Cortical neurons were separated and cultured from newborn (less than 24 h) Sprague Dawley(SD) rats. The method of FDA fluorescein staining was used to detect the viability of cortical neurons. Hoechst33258 nucleus staining and agarose gel electrophoresis were used to observe the characters of apoptosis. And SAPK/JNK assay kit was used to measure SAPK/JNK activity. RESULTS AlCl 3 (10-1000 μmol·L -1 ) decreased the viability and induced apoptosis of cortical neurons. The phosphorylation of SAPK/JNK increased significantly (4.2 times as compared to control, P<0.01), and the activity of SAPK/JNK was elevated when cortical neurons were cultured with 1000 μmol·L -1 AlCl 3 for 6 h. But when the cortical neurons were pretreated with CEP 11004 (1-10 μmol·L -1 ) for 6 h prior to treatment with 1000 μmol·L -1 AlCl 3 for 6 h, the phosphorylation of SAPK/JNK decreased significantly in a dose dependent manner (2.3, 1.2 and 0.9 times as compared to control respectively, P<0.05). It indicated the JNK inhibitor CEP 11004 promoted the survival of cortical neurons by blocking apoptosis and protected the neurons. CONCLUSION CEP 11004 inhibited the activation of SAPK/JNK to protect cortical neurons from apoptosis induced by aluminum chloride.

关 键 词：蛋白激酶抑制剂 CEP-11004 铝 神经元凋亡 神经退行性疾病 

分 类 号：R965[医药卫生—药理学]