Protective effect of Nrf2-ARE activator isolated from green perilla leaves on dopaminergic neuronal loss in a Parkinson's disease model

•DDC is a Nrf2-ARE activator derived from green perilla.•DDC protected 6-hydroxydopamine-induced dopaminergic neuronal loss.•DDC upregulated the expression of heme oxygenase-1 in glial cells.•GC/PKG pathway was involved in the protective effect of DDC.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN), and oxidative stress is thought to contribute to the pathogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, which is a cellular defense system against oxidative stress, is a promising target for therapeutics aimed at reducing neuronal death in PD. Previously, we have isolated 2′,3′-dihydroxy-4′,6′-dimethoxychalcone (DDC) from green perilla leaves as an activator of the Nrf2-ARE pathway. The present study showed the protective effect of DDC on PD models in vivo and in vitro. In a 6-hydroxydopamine (6-OHDA)-induced hemiparkinson's disease mouse model, intracerebral administration of DDC suppressed the dopaminergic neuronal loss and behavioral dysfunction. DDC upregulated the expression of heme oxygenase-1 (HO-1), one of the ARE-driven antioxidant enzymes, in astrocytes and microglia of the SN. In primary mesencephalic cultures, treatment with DDC also increased the HO-1 expression in astrocytes and microglia. DDC showed a protective effect against 6-OHDA-induced dopaminergic neuronal death, and the effect was suppressed by an HO-1 inhibitor. These results suggest that DDC prevents dopaminergic neurons from oxidative stress by upregulation of glial expression of HO-1.

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