title: Integrating Image-Based High-Content Screening with Mouse Models Identifies 5-Hydroxydecanoate as a Neuroprotective Drug for Paclitaxel-Induced Neuropathy.
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. This study aimed to discover potential neuroprotective drugs for paclitaxel-induced neurotoxicity. An image-based high-content platform was first developed to screen for potential neuroprotective drugs. The screening system comprised of automated image acquisition and multiparameter analysis, including neuronal viability, neurite outgrowth, and synaptogenesis. By this platform, we obtained a candidate list from compound libraries. In the drug screening from compound libraries of ion channel ligands, REDOX and GABAergic ligands, 5-hydroxydecanoate (5-HD) exhibited the most significant neuroprotective effects 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.
authors: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Li-Hsien
authors: LH
authors: Chen
authors: Department of Neurology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Internal Medicine, National Cheng Kung University Hospital Dou-Liou Branch, Yunlin, Taiwan. Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan.
authors: Yuan-Ting
authors: YT
authors: Sun
authors: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Yih-Fung
authors: YF
authors: Chen
authors: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Mei-Yi
authors: MY
authors: Lee
authors: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Lian-Yun
authors: LY
authors: Chang
authors: Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors: Jang-Yang
authors: JY
authors: Chang
authors: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan. Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. mrshen@mail.ncku.edu.tw.
authors: Meng-Ru
authors: MR
authors: Shen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017239:Paclitaxel / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D061251:Primary Cell Culture; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003652:Decanoic Acids; D006880:Hydroxy Acids; D018696:Neuroprotective Agents; C052853:5-hydroxydecanoic acid; D017239:Paclitaxel