Effects of an Nrf2-ARE activator isolated from green perilla leaves on ear swelling in a mouse contact hypersensitivity model

[Speaker] Yuka Takeda:1
[Co-author] Yuki Takada-Takatori:1, Yasuhiko Izumi:2, Akinori Akaike:2, Toshiaki Kume:2, Katsuharu Tsuchida:1
1:Department of Rational Medicinal Science, Faculty of Pharmaceutical Sciences, Doshisha Women's College, Japan, 2:Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan

Background: Contact dermatitis is an inflammatory skin disease resulting from direct contact of a substance with the surface of the skin, and oxidative stress is thought to contribute to the pathogenesis. One of the cellular defense systems against oxidative stress is the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Activation of this pathway increases the expression of antioxidant enzymes. Previously, we isolated 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC) from the ether extract of green perilla as an activator of the Nrf2-ARE pathway, and reported that DDC showed a protective effect against hydrogen peroxide-induced oxidative stress in human keratinocyte cell line. In this study, we examined the effects of DDC on swelling and morphological changes caused by contact hypersensitivity (CHS).
Methods: CHS was evoked by applying 1% picryl chloride (PCl) on the right ear of male ICR mice aged 4 weeks. The ear was sensitized with PCl (Day -7). 7 days after sensitization (Day 0), the same ear was exposed to PCl every 2 days for 12 days. The drug was administrated 2 hours after PCl treatment. The ear thickness was measured with a thickness gauge. Histological examination was performed by hematoxylin-eosin staining. A number of scratching of the ear was counted for 10 minutes. The induction of antioxidant enzymes was investigated by Western blotting.
Results: Ear swelling induced by PCl challenge was observed in a time-dependent manner. Histopathology showed the increased thickness of the dermis and epidermis. DDC (0.02 - 2 nmol) administration from Day 6 suppressed the ear swelling in a dose-dependent manner. DDC (0.02 - 2 nmol) administration from Day 0 or Day -7 suppressed the ear swelling in an administration period-dependent manner. The scratching count was suppressed in a dose-dependent manner of DDC. Furthermore, expression of antioxidant enzyme in the right ear was investigated for the purpose of examining the effectiveness of DDC. The expression levels of γ-GCS and HO-1 were increased for 24 hours after DDC administration.
Conclusions: These results suggest that DDC activates the Nrf2-ARE pathway and increases the expression of the antioxidant enzymes, which suppresses the inflammatory response in CHS.
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