Apomorphine protects against 6-hydroxydopamine-induced neuronal cell death through activation of the Nrf2-ARE pathway

J Neurosci Res. 2006 Sep;84(4):860-6. doi: 10.1002/jnr.20974.


NF-E2-related factor-2 (Nrf2), a basic leucine zipper transcription factor, is involved in the expression of numerous detoxifying and antioxidant genes via the antioxidant response element (ARE). Apomorphine (Apo), a dopamine D(1)/D(2) receptor agonist, is used for clinical therapy of Parkinson's disease. On the other hand, Apo is a potent radical scavenger and has protective effects on oxidative stress-induced cell death. Previously, we have reported that pretreatment of human neuroblastoma SH-SY5Y cells with Apo enhances protection against 6-hydroxydopamine (6-OHDA)-induced cell death. In this study, we investigated whether the Nrf2-ARE system is involved in the protection by Apo. Pretreatment of SH-SY5Y cells with Apo suppressed 6-OHDA-induced cell death in a dose-dependent manner. However, neither SCH23390, a dopamine D(1) receptor antagonist, nor sulpiride, a dopamine D(2) receptor antagonist, prevented the protective effect of Apo. Apo stimulated the translocation of Nrf2 into the nucleus and the transactivation of the ARE. The expression of heme oxygenase-1 (HO-1) was dose dependently induced by Apo. Moreover, we found that the activation of the ARE and the induction of HO-1 mRNA caused by Apo were suppressed in the presence of the antioxidant N-acetylcysteine and also that Apo produced intracellular reactive oxygen species (ROS), indicating that the low level of ROS produced by Apo may play a critical role in this phenomenon. Taken together, our findings suggest that not only the function as a radical scavenger but also the function as an Nrf2-ARE pathway activator may be involved in the neuroprotective effects of Apo.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / pharmacology*
  • Apomorphine / pharmacology*
  • Benzazepines / pharmacology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dopamine Agonists / pharmacology*
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Activation / drug effects
  • Flow Cytometry / methods
  • Heme Oxygenase-1 / metabolism
  • Humans
  • NF-E2-Related Factor 2 / metabolism*
  • Neuroblastoma
  • Oxidopamine / pharmacology*
  • RNA, Messenger / metabolism
  • Response Elements
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Signal Transduction / drug effects*


  • Adrenergic Agents
  • Benzazepines
  • Dopamine Agonists
  • Dopamine Antagonists
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Messenger
  • Oxidopamine
  • Heme Oxygenase-1
  • Apomorphine