[Molecular mechanism of neuroprotective drugs against oxidative stress-induced neuronal cell death].
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). Keap1, a cytoplasmic protein, sequesters Nrf2 in the cytoplasm under normal conditions. Various stimuli, including electrophiles and oxidative stress, liberate Nrf2 from Keap1, allowing Nrf2 to translocate into the nucleus and to bind to the ARE. Recently, there is increasing evidence that compounds that stimulate the activation of the Nrf2-ARE pathway may become useful therapeutic drugs for neurodegenerative diseases associated with oxidative stress. 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. We previously reported that pretreatment of human neuroblastoma SH-SY5Y cells with Apo enhanced the protective effects. In addition, we have recently demonstrated that Apo stimulates the translocation of Nrf2 into the nucleus and the transactivation of the ARE. 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 on oxidative stress-induced neuronal cell death. In this review, our recent studies on the mechanism underlying Apo-induced neuroprotection are summarized.
Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Japan. harah@gifu-pu.ac.jp
Hirokazu
H
Hara
D000975:Antioxidants; D001058:Apomorphine / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use; D016166:Free Radical Scavengers; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000209:etiology*; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000502:physiology*; D020218:Response Elements / Q000502:physiology
D000975:Antioxidants; D018491:Dopamine Agonists; D016166:Free Radical Scavengers; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D001058:Apomorphine