Scutellarein attenuates atopic dermatitis by selectively inhibiting transient receptor potential vanilloid 3 channels

Yujing Wang1 | Liaoxi Tan1 Shan Jiang1 | Younan Ren1 Khalid N. M. Abdelazeem4 | Zhengyu Cao1

| Kejun Jiao1 | Chu Xue1 | Qinglian Tang1 | | Hao Chen2 | Tarek Mohamed Abd El-Aziz3 |

Ye Yu5 | Fang Zhao1 | Michael X. Zhu6 |
1State Key Laboratory of Natural Medicines and Department of TCM Pharmacology, School of Traditional Chinese Pharmacy, China Pharmaceutical University,

Nanjing, China
2Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
3Zoology Department, Faculty of Science, Minia University, El-Minia, Egypt
4Radiation Biology Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
5Department of Basic Medicine, School of Basic Medicine and Clinic Pharmacy, China Pharmaceutical University, Nanjing, China
6Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA

Background and Purpose: Atopic dermatitis (AD) is one of the most common chronic inflammatory cutaneous diseases with unmet clinical needs. As a common ingredient found in several medicinal herbs with efficacy on cutaneous inflammatory diseases, Scutellarein (Scu) has been shown to possess anti-inflammatory and anti-proliferative activities. We aimed to evaluate the therapeutic efficacy of Scu against AD and its underlying molecular mechanism.

Experimental Approach: Efficacy of Scu on AD was evaluated in 2,4-dinitrofluorobenzene (DNFB) and carvacrol-induced dermatitis mouse models. Cytokine mRNA and serum IgE levels were examined using qPCR and ELISA, respec- tively. Voltage clamp recordings were used to measure currents mediated by tran- sient receptor potential (TRP) channels. In silico docking, site-direct mutagenesis, and covalent modification were used to explore the binding pocket of Scu on TRPV3.

Key Results: Subcutaneous administration of Scu efficaciously suppresses DNFB and carvacrol-induced pruritus, epidermal hyperplasia and skin inflammation in wild type mice but has no additional benefit in Trpv3 knockout mice in the carvacrol model. Scu is a potent and selective TRPV3 channel allosteric negative modulator with an appar- ent affinity of 1.18 μM. Molecular docking coupled with site-direct mutagenesis and covalent modification of incorporated cysteine residues demonstrate that Scu targets the cavity formed between the pore helix and transmembrane helix S6. Moreover, Scu attenuates endogenous TRPV3 activity in human keratinocytes and inhibits carvacrol-induced proliferative and proinflammatory responses.

Conclusion and Implications: Collectively, these data demonstrate that Scu amelio- rates carvacrol-induced skin inflammation by directly inhibiting TRPV3, and TRPV3 represents a viable therapeutic target for AD treatment.

KEYWORDS

atopic dermatitis, keratinocytes, scutellarein, TRPV3