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

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.
AuthorsHirokazu Hara, Mitsuhiro Ohta, Tetsuo Adachi
JournalJournal of neuroscience research (J Neurosci Res) Vol. 84 Issue 4 Pg. 860-6 (Sep 2006) ISSN: 0360-4012 [Print] United States
PMID16802348 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adrenergic Agents
  • Benzazepines
  • Dopamine Agonists
  • Dopamine Antagonists
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Messenger
  • Oxidopamine
  • Heme Oxygenase-1
  • Apomorphine
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: