2. Academic Validation
  3. The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling

The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling

  • Acta Pharmacol Sin. 2021 Apr;42(4):593-603. doi: 10.1038/s41401-020-0484-5.
Fang-Ming Yang 1 2,  Di Fan 1 2,  Xiao-Qian Yang 2,  Feng-Hua Zhu 2,  Mei-Juan Shao 1 2,  Qian Li 2,  Yu-Ting Liu 2 3,  Ze-Min Lin 2,  Shi-Qi Cao 2 3,  Wei Tang 2 3,  Shi-Jun He 4 5,  Jian-Ping Zuo 6 7 8
Affiliations

Affiliations

  • 1 Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 2 Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. heshijun@simm.ac.cn.
  • 5 University of Chinese Academy of Sciences, Beijing, 100049, China. heshijun@simm.ac.cn.
  • 6 Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. jpzuo@simm.ac.cn.
  • 7 Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jpzuo@simm.ac.cn.
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, China. jpzuo@simm.ac.cn.
PMID: 32747720 DOI: 10.1038/s41401-020-0484-5
Abstract

Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by manifestations of dryness and irritation. Although the pathogenesis is not fully illuminated, it is recognized that inflammation has a prominent role in the development and deterioration of DED. β-aminoarteether maleate (SM934) is a water-soluble artemisinin derivative with anti-inflammatory and immunosuppressive activities. In this study, we established scopolamine hydrobromide (SCOP)-induced rodent model as well as benzalkonium chloride (BAC)-induced rat model to investigate the therapeutic potential of SM934 for DED. We showed that topical application of SM934 (0.1%, 0.5%) significantly increased tear secretion, maintained the number of conjunctival goblet cells, reduced corneal damage, and decreased the levels of inflammatory mediators (TNF-α, IL-6, IL-10, or IL-1β) in conjunctiva in SCOP-induced and BAC-induced DED models. Moreover, SM934 treatment reduced the accumulation of TLR4-expressing macrophages in conjunctiva, and suppressed the expression of inflammasome components, i.e., myeloid differentiation factor88 (MyD88), Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and cleaved Caspase 1. In LPS-treated RAW 264.7 cells, we demonstrated that pretreatment with SM934 (10 μM) impeded the upregulation of TLR4 and downstream NF-κB/NLRP3 signaling proteins. Collectively, artemisinin analog SM934 exerts therapeutic benefits on DED by simultaneously reserving the structural integrity of ocular surface and preventing the corneal and conjunctival inflammation, suggested a further application of SM934 in ophthalmic therapy, especially for DED.

Keywords

TLR4; artemisinin derivative; dry eye disease; inflammasome; inflammation; macrophages; β-aminoarteether maleate.

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