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发现潜在的神经保护剂对抗紫杉醇诱导的周围神经病。

Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy.

机构信息

Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City 70101, Taiwan, R. O. C.

Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 70101, Taiwan, R. O. C.

出版信息

J Med Chem. 2022 Mar 24;65(6):4767-4782. doi: 10.1021/acs.jmedchem.1c01912. Epub 2022 Mar 2.

DOI:10.1021/acs.jmedchem.1c01912
PMID:35234475
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8958505/
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.

摘要

化疗引起的神经毒性是癌症治疗的常见不良反应。目前还没有药物被证明能有效预防或治疗化疗引起的神经毒性。本研究以米诺地尔为初始模板进行结构修饰，结合体外神经突生长测定、基于图像的高通量筛选平台和小鼠行为模型，发现了一种有效的神经保护剂 CN016。我们的结果表明，CN016 能显著抑制紫杉醇诱导的炎症反应和免疫细胞浸润到感觉神经元。因此，抑制促炎因子部分阐明了 CN016 缓解紫杉醇诱导的周围神经病的作用机制。基于改善行为功能的优异疗效、在小鼠中具有高安全性（MTD > 500mg/kg）和大治疗窗（MTD/MED > 50），CN016 有可能成为一种外周神经保护剂，以预防以紫杉醇为代表的化疗药物引起的神经毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/50f98da74b0e/jm1c01912_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/ab53a5f85f88/jm1c01912_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/face327b4732/jm1c01912_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/1794912366c9/jm1c01912_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/d1eb0df1899a/jm1c01912_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/537ec30988a8/jm1c01912_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/cf2b2a498455/jm1c01912_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/eeb50cbbf9d5/jm1c01912_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/cc75b46ffa26/jm1c01912_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/4fe1f40e9ec5/jm1c01912_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/50f98da74b0e/jm1c01912_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/ab53a5f85f88/jm1c01912_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/face327b4732/jm1c01912_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/1794912366c9/jm1c01912_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/d1eb0df1899a/jm1c01912_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/537ec30988a8/jm1c01912_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/cf2b2a498455/jm1c01912_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/eeb50cbbf9d5/jm1c01912_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/cc75b46ffa26/jm1c01912_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/4fe1f40e9ec5/jm1c01912_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84c5/8958505/50f98da74b0e/jm1c01912_0010.jpg

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