Volume 31 Issue 2 - December 2, 2016 PDF
Integrating image-based high-content screening with mouse models identifies 5-hydroxydecanoate as a Neuroprotective drug for paclitaxel-induced neuropathy
Li-Hsien Chen1,Yuan-Ting Sun2,3,4, Yih-Fung Chen1,5, Mei-Yi Lee1,
Lian-Yun Chang1, Jang-Yang Chang6,7, and Meng-Ru Shen1,4,8,*
1Department of Pharmacology, College of Medicine, National Cheng Kung University,Tainan,Taiwan
2Department of Neurology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3Department of Internal Medicine, National Cheng Kung University Hospital Dou-Liou Branch,Yunlin,Taiwan
4Advanced Optoelectronic Technology Center, NationalCheng KungUniversity,Tainan,Taiwan
5Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung,Taiwan
6Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
7National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
8Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Neurotoxicity is a common complication in cancer patients receiving chemotherapy. Effective neuroprotective drugs against chemotherapy are not available so far. Current strategies for evaluating chemical-induced neurotoxicity include in vitro examination of morphologic and functional changes in neurons, and in vivo assessment of neuropathologic and behavioral endpoints in rodent species. This study aims to develop an image-based high-content platform and a mouse model for the discovery of potential neuroprotective drugs against chemotherapy. Using this high-content platform to screen compounds from drug libraries of ion channel ligands, REDOX (portmanteau of reduction and oxidation), and GABAergic ligands, we identified 5-hydroxydecanoate (5-HD) as a novel neuroprotective drug against paclitaxel-induced neurotoxicity in both cortical and dorsal root ganglion (DRG) neurons. In mouse behavioral tests, 5-HD restored the thermal sensitivity and alleviated mechanical allodynia induced by paclitaxel. Electron micrographs of sciatic nerve revealed that 5-HD reduced the damages caused by paclitaxel in the nonmyelinated and smaller myelinated fibers. The mechanistic study on DRG neurons suggested that 5-HD rescued the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, 5-HD did not jeopardize the antitumor effect of paclitaxel in tumor xenograft models. In conclusion, we established an imaged-based high-content screening platform and a protocol for verifying the neuroprotective effect in vivo, by which 5-HD was identified and validated as a potential neuroprotective drug for paclitaxel-induced neuropathy.
Neuroprotective drugs screened from the image-based high-content platform. Representative images show that 5-HD is a potential neuroprotective drug in the cell model of cortical neurons.
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