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

Abstract
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
Topics
  • 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)

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