Download 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

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.