Enantio-selective inhibition of (1R,9S)- and (1S,9R)-β-hydrastines on dopamine biosynthesis in PC12 cells
Enantio-selective inhibition of (1R,9S)- and (1S,9R)-β-hydrastines on dopamine biosynthesis in PC12 cells
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DOI：
10.1016/j.neuropharm.2004.07.033
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发表时间：
2004-12
影响因子：
4.7
通讯作者：
S. Yin;Y. M. Kim;Jae Joon Lee;C. Jin;Y. Yang;J. Ma;Min H. Kang;M. Kai;Myung-Koo Lee
中科院分区：
文献类型：
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作者：
S. Yin;Y. M. Kim;Jae Joon Lee;C. Jin;Y. Yang;J. Ma;Min H. Kang;M. Kai;Myung-Koo Lee
研究了β-水合碱（BHS） (1R,9S)-和(1S,9R)-对映体对PC12细胞多巴胺生物合成的抑制作用。（1R,9S）-BHS在24 h时降低了细胞内多巴胺含量，ic50值为14.3 μM，而(1S,9R)-BHS则无此作用。（1R,9S）-BHS在250 μM浓度下对PC12细胞无细胞毒性。在这些条件下，(1R,9S)-BHS主要以浓度依赖性方式抑制酪氨酸羟化酶（TH）活性（20 μM抑制33%），并降低PC12细胞TH mRNA水平。（1R,9S）-BHS对多巴胺含量和TH活性的抑制模式具有相似的行为曲线。（1R,9S）-BHS在10-50 μM下也能降低细胞内环AMP水平和Ca2+浓度。此外，与对照组相比，20-50 μM l-DOPA处理24 h可使PC12细胞内多巴胺含量增加198-251%。然而，当l-DOPA与(1R,9S)-BHS （10-50 μM）联用时，l-DOPA （20-50 μM）诱导的多巴胺水平升高降低。这些结果表明，(1R,9S)-BHS而不是(1S,9R)-BHS降低了多巴胺含量，并通过抑制PC12细胞中TH活性和TH基因表达而诱导了左旋多巴胺含量的增加，从而证明(1R,9S)-BHS具有调节多巴胺生物合成的功能。
The inhibitory effects of (1R,9S)- and (1S,9R)-enantiomers of β-hydrastine (BHS) on dopamine biosynthesis in PC12 cells were investigated. (1R,9S)-BHS decreased the intracellular dopamine content with the IC50value of 14.3 μM at 24 h, but (1S,9R)-BHS did not. (1R,9S)-BHS was not cytotoxic at concentrations up to 250 μM towards PC12 cells. In these conditions, (1R,9S)-BHS inhibited tyrosine hydroxylase (TH) activity mainly in a concentration-dependent manner (33% inhibition at 20 μM) and decreased TH mRNA level in PC12 cells. The inhibitory patterns of dopamine content and TH activity by (1R,9S)-BHS showed similar behavioral curves. (1R,9S)-BHS at 10–50 μM also reduced the intracellular cyclic AMP level and Ca2+concentration. In addition, treatment of l-DOPA at 20–50 μM for 24 h increased the intracellular dopamine content to 198–251% compared with the control in PC12 cells. However, the increase in dopamine levels induced by l-DOPA (20–50 μM) was reduced when l-DOPA was combined with (1R,9S)-BHS (10–50 μM). These results indicate that (1R,9S)-BHS, but not (1S,9R)-BHS, reduced dopamine content and l-DOPA-induced increase in dopamine content, in part, through the inhibition of TH activity and TH gene expression in PC12 cells: thus, (1R,9S)-BHS proved to have a function to regulate dopamine biosynthesis.