2. Academic Validation
  3. Usnic acid derivatives as tau-aggregation and neuroinflammation inhibitors

Usnic acid derivatives as tau-aggregation and neuroinflammation inhibitors

  • Eur J Med Chem. 2020 Feb 1;187:111961. doi: 10.1016/j.ejmech.2019.111961.
Cun-Jian Shi 1,  Wan Peng 1,  Jin-Hua Zhao 1,  Hua-Li Yang 1,  Lai-Liang Qu 1,  Cheng Wang 1,  Ling-Yi Kong 2,  Xiao-Bing Wang 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: cpu_lykong@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xbwang@cpu.edu.cn.
PMID: 31865017 DOI: 10.1016/j.ejmech.2019.111961
Abstract

Accumulation of Tau Protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation. The inhibitory activity of the derivatives against the self-fibrillation of the hexapeptide AcPHF6 was initially screened by ThT fluorescence assay. Using circular dichroism and transmission electron microscopy, compound 30 showed the most potent inhibitory activity against AcPHF6 self-fibrillation. Compound 30 was further confirmed to inhibit the aggregation of full-length 2N4R Tau Protein by a heparin-induced mechanism. In addition, we investigated the anti-inflammatory activity of compound 30, and showed that compared with sodium usnate, it reduced NO release in LPS-stimulated mouse microglia BV2 cells. More importantly, 30 showed significant protective effects against okadaic acid-induced memory impairment in rats. Thus, 30 was a novel tau-aggregation and neuroinflammation inhibitor that represented a potential therapeutic candidate for AD.

Keywords

Alzheimer’s disease; Anti-inflammatory; Tau anti-aggregation; Usnic acid derivatives.

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