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.

• Authors: Hirokazu Hara, Mitsuhiro Ohta, Tetsuo Adachi
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 84 Issue 4 Pg. 860-6 (Sep 2006) ISSN: 0360-4012 [Print] United States
• PMID: 16802348 (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)