L-DOPA modulates cell viability through the ERK-c-Jun system in PC12 and dopaminergic neuronal cells

Neuropharmacology. 2016 Feb:101:87-97. doi: 10.1016/j.neuropharm.2015.09.006. Epub 2015 Sep 9.

Abstract

L-DOPA causes neurotoxicity by modulating the Epac-ERK system in PC12 cells. This study investigated the effects of a single treatment with L-DOPA and multiple treatments with L-DOPA (MT-LD) on ERK1/2 and JNK1/2-c-Jun systems. In PC12 cells, a toxic L-DOPA concentration (200 μM) induced sustained ERK1/2 and JNK1/2 phosphorylation that was inhibited by the Epac inhibitor brefeldin A, but not by the PKA inhibitor H89. This ERK1/2 and JNK1/2 phosphorylation was also inhibited by ERK1/2 (U0126) and JNK1/2 (SP600125) inhibitors, respectively, but sustained ERK1/2 phosphorylation was not affected by JNK1/2 phosphorylation. A non-toxic L-DOPA concentration (20 μM) induced c-Jun phosphorylation (Ser73) via transient ERK1/2 phosphorylation, whereas the toxic L-DOPA concentration induced c-Jun phosphorylation (Ser63) and c-Jun expression via Epac-sustained ERK1/2-JNK1/2 phosphorylation, which then enhanced cleaved caspase-3 expression. MT-LD (20 μM) initially enhanced c-Jun phosphorylation (Ser73) (for 1-4 days), but later (5-6 days) induced c-Jun phosphorylation (Ser63) and c-Jun expression. In the 6-hydroxydopamine-lesioned rat model of Parkinson's disease, L-DOPA administration (10 mg/kg) protected against neurotoxicity through c-Jun phosphorylation (Ser73) for 1-2 weeks. However, L-DOPA administration (10 or 30 mg/kg) showed neurotoxicity through c-Jun phosphorylation (Ser63) and c-Jun expression via ERK1/2 phosphorylation for 3-4 weeks. Thus, in PC12 cells, non-toxic L-DOPA treatment maintained cell survival through c-Jun phosphorylation (Ser73). By contrast, toxic L-DOPA treatment or MT-LD (20 μM) induced c-Jun phosphorylation (Ser63) and c-Jun expression via Epac-dependent sustained ERK1/2 and JNK1/2 phosphorylation, which subsequently led to cell death. These results were validated by those obtained after long-term L-DOPA administration in a rat model of Parkinson's disease. Our data indicate that L-DOPA causes neurotoxicity via the ERK1/2-c-Jun system in dopaminergic neuronal cells.

Keywords: ERK1/2; Epac; L-DOPA; PC12 cells; Rat model of Parkinson's disease; c-Jun.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / toxicity
  • Animals
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Dopamine Agents / pharmacology*
  • Dopaminergic Neurons / drug effects*
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Levodopa / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Mesencephalon / cytology
  • Oxidopamine / toxicity
  • PC12 Cells
  • Parkinson Disease / etiology
  • Parkinson Disease / pathology
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors

Substances

  • Adrenergic Agents
  • Dopamine Agents
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-jun
  • Levodopa
  • Oxidopamine
  • Caspase 3