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開發神經保護劑以預防及治療化學藥物引起週邊神經病變 Discovery of neuroprotective drugs to prevent and treat chemotherapy-induced peripheral neuropathy Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect commonly observed in cancer patients. No effective medication is approved for the prevention or treatment of CIPN in large randomized, placebo-controlled clinical trials. We are interested in the discovery of potential neuroprotective drugs for CIPN. An image-based high-content screening platform was first developed. The platform comprised of automated image acquisition and multi-parameter analysis, including neuronal viability, neurite outgrowth and synaptogenesis. By this platform, the lead compounds and specific monoclonal antibodies were selected and tested for their neuroprotective effect on paclitaxel-induced neurotoxicity in vivo. Lead compound A and monoclonal antibody B for specific cytokine exhibited the most significant neuroprotective effects against paclitaxel-induced neurotoxicity. Both of them restored the thermal sensitivity and alleviated mechanical allodynia induced by paclitaxel in mouse behavioral test. Electron micrographs of sciatic nerve revealed that compound A and monoclonal antibody B reduced the small myelinated and non-myelinated fibers damages induced by paclitaxel. The mechanistic study on dorsal root ganglion suggested that compound A rescued the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, compound A and monoclonal antibody B 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 the lead compounds were identified and validated as a potential neuroprotective drugs for CIPN.