title: [Dopaminergic neuroprotection via Nrf2-ARE pathway activation: identification of an activator from green perilla leaves].
abstract: Parkinson disease is one of the most common neurodegenerative disorders and is characterized by the selective loss of dopaminergic neurons in the substantia nigra. Although a decrease in proteasome activity has been found in patients with sporadic Parkinson disease, the relationship between the ubiquitin-proteasome system and dopaminergic neuronal death remains to be elucidated. Here, we review a mechanism in which proteasome inhibition provides dopaminergic neuroprotection from oxidative stress. Treatment with lactacystin, a proteasome inhibitor, significantly suppressed 6-hydroxydopamine (6-OHDA)-induced toxicity and oxidative stress in PC12 cells. In addition, lactacystin enhanced glutathione synthesis via elevation of γ-glutamylcysteine synthetase (γ-GCS) mRNA levels. Expression of antioxidant enzymes, such as γ-GCS and hemeoxygenase-1 (HO-1), is regulated by the nuclear factor-erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Lactacystin induced Nrf2 accumulation and increased ARE activity. In mesencephalic cultures, lactacystin-induced upregulation of HO-1 in astrocytes contributed to dopaminergic neuroprotection against 6-OHDA-induced toxicity. These data suggest that proteasome inhibition provides cytoprotection against oxidative stress by activating the Nrf2-ARE pathway. Subsequently, we attempted to identify a novel Nrf2-ARE activator in dietary fruits and vegetables. Using bioactivity-guided fractionation, we identified 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC) from green perilla leaves as the activator responsible for the increased activation of the ARE pathway. DDC upregulated γ-GCS and HO-1 and protected PC12 cells against 6-OHDA-induced toxicity. In conclusion, the activation of the Nrf2-ARE pathway may be an effective means to prevent dopaminergic neuronal death in patients with Parkinson disease.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. yizumi@pharm.kyoto-u.ac.jp
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D061745:Antioxidant Response Elements / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D047188:Chalcones / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine / Q000037:antagonists & inhibitors; D010300:Parkinson Disease / Q000473:pathology; D031343:Perilla / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D051381:Rats
chemical_list: C576910:2',3'-dihydroxy-4',6'-dimethoxychalcone; D047188:Chalcones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C067713:lactacystin; D016627:Oxidopamine; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine