Modulatory effects of sesamin on dopamine biosynthesis and l-DOPA-induced cytotoxicity in PC12 cells

Abstract

The effects of sesamin on dopamine biosynthesis and l-DOPA-induced cytotoxicity in PC12 cells were investigated. Sesamin at concentration ranges of 20–75 μM exhibited a significant increase in intracellular dopamine levels at 24 h: 50 μM sesamin increased dopamine levels to 133% and tyrosine hydroxylase (TH) activity to 128.2% of control levels. Sesamin at 20–100 μM rapidly increased the intracellular levels of cyclic AMP (cAMP) to 158.3%–270.3% of control levels at 30 min. At 50 μM, sesamin combined with l-DOPA (50, 100 and 200 μM) further increased the intracellular dopamine levels for 24 h compared to l-DOPA alone. In the absence or presence of l-DOPA (100 and 200 μM), sesamin (50 μM) 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 h, an effect which was reduced by l-DOPA (100 and 200 μM). In addition, 50 μM sesamin exhibited a protective effect against l-DOPA (100 and 200 μM)-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 μM)-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.