Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy

Yi Fan Chen, Chien Huang Wu, Li Hsien Chen, Hao Wei Lee, Jinq Chyi Lee, Teng Kuang Yeh, Jang Yang Chang, Ming Chen Chou, Hui Ling Wu, Yen Po Lai, Jen Shin Song, Kai Chia Yeh, Chiung Tong Chen, Chia Jui Lee, Kak Shan Shia, Meng Ru Shen

Research output: Contribution to journalArticlepeer-review

Abstract

Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. Using minoxidil as an initial template for structural modifications in conjunction with an in vitro neurite outgrowth assay, an image-based high-content screening platform, and mouse behavior models, an effective neuroprotective agent CN016 was discovered. Our results showed that CN016 could inhibit paclitaxel-induced inflammatory responses and infiltration of immune cells into sensory neurons significantly. Thus, the suppression of proinflammatory factors elucidates, in part, the mechanism of action of CN016 on alleviating paclitaxel-induced peripheral neuropathy. Based on excellent efficacy in improving behavioral functions, high safety profiles (MTD > 500 mg/kg), and a large therapeutic window (MTD/MED > 50) in mice, CN016 might have great potential to become a peripherally neuroprotective agent to prevent neurotoxicity caused by chemotherapeutics as typified by paclitaxel.

Original languageEnglish
Pages (from-to)4767-4782
Number of pages16
JournalJournal of Medicinal Chemistry
Volume65
Issue number6
DOIs
Publication statusPublished - Mar 24 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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