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

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.

Graphical abstractSesamin in PC12 cells• Enhanced Dopamine biosynthesis by TH activity and TH gene expression mediated by cAMP-PKA-CREB systems.• Protected against l-DOPA-induced cytotoxicity by the suppression of ROS activity via ERK1/2, BadSer112, Bcl-2, and caspase-3 pathways.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Sesamin enhanced dopamine biosynthesis in PC12 cells via cAMP-PKA-CREB systems. ► Sesamin also protected against l-DOPA-induced oxidative cytotoxicity. ► Anti-oxidative functions of sesamin were medicated by ERK1/2-Bad-Bcl-2-caspase-3 pathways. ► Sesamin might serve as an adjuvant phytonutrient for neurodegenerative diseases.