Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy
Yifan Chen, Chien-Huang Wu, Li‐Hsien Chen, Hao-Wei Lee, Jinq‐Chyi Lee, Teng‐Kuang Yeh, Jang‐Yang Chang, Ming‐Chen Chou, Huiling Wu, Yen-Po Lai, Jen‐Shin Song, Kai‐Chia Yeh, Chiung‐Tong Chen, Chia‐Jui Lee, Kak‐Shan Shia, Meng-Ru Shen
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.