서강대학교

초록/요약

Parkinson’s disease (PD) is a neurodegenerative disorder affecting 1% of the population above the age of 60. It is associated with a selective loss of dopaminergic neurons in the substantia nigra pars compacta. Because oxidative stress caused by dopamine oxidation to dopamine quinone is suggested as a major factor contributing to the pathogenesis of PD, the induction of the enzyme that catalyzed the reduction of quinone, quinine reductase (QR), could be a desirable therapeutic strategy to protect cells from oxidative damage. The transcription factor nuclear, Nrf2, regulates the expression of antioxidant enzymes via the antioxidant response element. The Nrf2 is inactive since it is sequestered in the cytoplasm by its repressor Kelch-like ECH-associated protein 1 (Keap1). In response to other reactive chemicals, cysteine residues in Keap1 are modified, resulting in a conformational change that releases and activates Nrf2. Activated Nrf2 is transported to the nucleus where it binds to promoters, antioxidant response element (ARE). Binding of Nrf2 to the ARE upregulates transcription of cytoprotective enzymes, NQO-1, HO-1. A wide variety of dietary and synthetic compounds that function as potent inducers of ARE-regulated gene expression (eg., sulforaphane, curcumin and gallic acid) have been shown to exert chemopreventive activities. Specially, sulforaphane showed protective effect against dopaminergic cell death. However it also exhibited cytotoxicity due to isothiocyanate group. In this study, sulforaphane derivatives were synthesized and tested their NO inhibition and HO-1 inducing activities in BV2 cell. Among them, the compound 26b-1 showed potent activities for both HO-1 induction and inhibition of NO production in a dose dependent manner. Furthermore, the compound 26b-1 led to significant increases in mRNA and protein levels of HO-1 and NQO1 in the cell. Finally, surface plasmon resonance (SPR) was used to directly measure the affinity of the interaction of Keap1 for the compound 26b-1 (Kd = 26.2 nM). These results indicate that the compound 26b-1 may induce NQO1 gene expression through binding to Keap1, which can lead to protection against DAergic cell death.