Dopaminergic Neuroprotection <i>via</i> 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.