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.
Hara
Hirokazu
H
Department of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan.
Ohta
Mitsuhiro
M
Adachi
Tetsuo
T
D018663:Adrenergic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry / Q000379:methods; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009447:Neuroblastoma; D016627:Oxidopamine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects*
D018663:Adrenergic Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D016627:Oxidopamine; D051547:Heme Oxygenase-1; D001058:Apomorphine