组蛋白去乙酰基酶抑制剂NL101对大鼠神经元的作用

Effect of histone deacetylase inhibitor NL101 on rat neurons

目的：观察组蛋白去乙酰基酶新抑制剂NL101对同型半胱氨酸（HCA）诱导大鼠神经元毒性损伤的保护作用,以及对正常神经元的损伤作用.方法：使用HCA（5 mmol/L）诱导大鼠皮层混合细胞及原代神经元的损伤,观察不同浓度NL101对损伤的影响,检测神经元及胶质细胞的活性、数量、形态以及坏死的变化,并观察NL101对正常神经元的作用;以同类药SAHA（suberoylanilide hydroxamic acid）作为对照.结果：0.001 ～ 10 μmol/L的NL101对HCA诱导的皮层混合细胞数量减少没有明显影响;但1、10 μmol/L的NL101可明显减少细胞坏死（P＜0.05）;1μmol/L的NL101可增加神经元数量.1、10μmol/L的NL101可明显降低原代神经元活性（均P ＜0.05）;但0.01 ～ 10 μmol/L的NL101可显著减轻HCA诱导的神经元活性降低（均P＜0.05）;1、10 μmol/L的NL101可减少HCA引起的神经元坏死（均P ＜0.05）.NL101的作用与SAHA大致相当.结论：NL101对HCA诱导的神经元损伤有保护作用,高浓度NL101对神经元有明显的毒性作用,与经典的SAHA作用相似.

Objective：To investigate the protective effect of histone deacetylase inhibitor NL101 on L-homocysteine （HCA）-induced toxicity in rat neurons,and the toxic effect on normal rat neurons.Methods：In the presence of NL101 at various concentrations,HCA （5 mmol/L）-induced changes in cell density,necrosis,and viability were determined in the mixed cultures of rat cortical cells and the primary cultures of rat neurons.The direct effect of NL101 on primary neurons was also observed in the absence of HCA.Histone deacetylase inhibitor suberoylanilide hydroxamic acid （SAHA） was used as the control.After the treatments,cell viability,the density,and morphology of neurons and glial cells,and cell necrosis were determined.Results：In the mixed cultures of cortical cells,NL101 had no effect on HCA （5 mmol/L）-induced cell number reduction at 0.001-10 μmol/L; however,it significantly attenuated necrosis at 1-10 μmol/L,and increased neuronal number at 1 μmol/L.NL101 had no effect on the mixed cortical cells in the absence of HCA.In the primary neurons,NL101 reduced neuronal viability and mildly increased necrosis at 1-10 μmol/L in the absence of HCA,while it significantly attenuated HCA-induced neuronal viability reduction at 0.01-10 μmol/L and reduced neuronal necrosis at 1-10 μmol/L.The effects of NL101 were apparently similar to those of SAHA.Conclusion：NL101 has protective effect on HCA-induced neuronal injury but it is neurotoxic at high concentrations,which is similar to the typical histone deacetylase inhibitor SAHA.