Modulatory effects of sesamin on dopamine biosynthesis and l-DOPA-induced cytotoxicity in PC12 cells
- 作者：Min Zhang ; Hak Ju Lee ; Keun Hong Park ; Hyun Jin Park ; Hyun Sook Choi ; Sung Cil Lim ; Myung Koo Lee ; myklee@chungbuk.ac.kr
- 关键词：Sesamin ; Dopamine biosynthesis ; l-DOPA-induced cytotoxicity ; Cyclic AMP ; PC12 cells
- 刊名：Neuropharmacology
- 出版年：2012
- 期刊代码：33_00283908
- 类别：pha
- 出版时间：June, 2012
- 卷：62
- 期：7
- 页码：2219-2226
- 文件大小：1275 K
摘要
The effects of sesamin on dopamine biosynthesis and l-DOPA-induced cytotoxicity in PC12 cells were investigated. Sesamin at concentration ranges of 20-75聽渭M exhibited a significant increase in intracellular dopamine levels at 24聽h: 50聽渭M sesamin increased dopamine levels to 133%and tyrosine hydroxylase (TH) activity to 128.2%of control levels. Sesamin at 20-100聽渭M rapidly increased the intracellular levels of cyclic AMP (cAMP) to 158.3%-270.3%of control levels at 30聽min. At 50聽渭M, sesamin combined with l-DOPA (50, 100 and 200聽渭M) further increased the intracellular dopamine levels for 24聽h compared to l-DOPA alone. In the absence or presence of l-DOPA (100 and 200聽渭M), sesamin (50聽渭M) increased the phosphorylation of TH, cAMP-dependent protein kinase (PKA), and cAMP-response element-binding protein (CREB), as well as the mRNA levels of TH and CREB for 24聽h, an effect which was reduced by l-DOPA (100 and 200聽渭M). In addition, 50聽渭M sesamin exhibited a protective effect against l-DOPA (100 and 200聽渭M)-induced cytotoxicity via the inhibition of reactive oxygen species (ROS) production and superoxide dismutase reduction, induction of extracellular signal-regulated kinase (ERK)1/2 and BadSer112 phosphorylation and Bcl-2 expression, and inhibition of cleaved-caspase-3 formation. These results suggested that sesamin enhanced dopamine biosynthesis and l-DOPA-induced increase in dopamine levels by inducing TH activity and TH gene expression, which was mediated by cAMP-PKA-CREB systems. Sesamin also protected against l-DOPA (100-200聽渭M)-induced cytotoxicity through the suppression of ROS activity via the modulation of ERK1/2, BadSer112, Bcl-2, and caspase-3 pathways in PC12 cells. Therefore, sesamin might serve as an adjuvant phytonutrient for neurodegenerative diseases.