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

✍ Scribed by Hirokazu Hara; Mitsuhiro Ohta; Tetsuo Adachi

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 272 KB
• Volume: 84
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.20974

✦ Synopsis

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. © 2006 Wiley‐Liss, Inc.