Myung Koo Lee
Chungbuk National University, Republic of Korea
Title: The role of cyclic AMP-ERK-c-Jun pathways on L-DOPA-induced neurotoxicity in neuronal and PC12 cells and the in vivo applications
Biography
Biography: Myung Koo Lee
Abstract
Parkinson’s disease (PD) causes by the degeneration of dopamine neurons in the substantia nigra. L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most frequently prescribed drug for controlling the symptoms of PD. However, the high levels of L-DOPA lead to cell death by generating reactive oxygen species in dopamine neurons and PC12 cells. The intracellular levels of cyclic AMP (cAMP) increase in response to cytotoxic concentrations of L-DOPA in PC12 cells, and multiple treatments with non-toxic L-DOPA (MT-LD) reduce dopamine biosynthesis in PC12 cells. We therfore investigated the effects of L-DOPA on ERK1/2 and JNK1/2-c-Jun systems. MT-LD (10 and 20 µM) induced cell survival via PKA-transient ERK1/2 activation in PC12 cells. MT-LD also induced differentiation via the Epac-sustained ERK1/2-c-Jun system, which subsequently led to the activation of the cell death process. In addition, SE and GP-EX enhanced dopamine biosynthesis and L-DOPA-induced increase in dopamine levels by inducing TH activity and TH gene expression in PC12 cells. SE and GP-EX protected L-DOPA-induced cytotoxicity through the modulation of the oxidative stress-induced cell death signaling pathways in PC12 cells. SE and GP-EX also showed the prophylactic and adjuvant therapeutic effects on long-term L-DOPA therapy in 6-hydroxydopamine-lesioned rat model of PD, suggesting that SE and GP-EX might serve as an adjuvant phytonutrient for PD. Taken together, it has been proposed that chronic treatment of L-DOPA led to the neurotoxic process via the cAMP-sustained ERK-c-Jun system and the modulation of ERK activity might be applied for screening the anti-neurodegenerative agents.