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 imagebased 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.

Minoxidil is a potential neuroprotective drug for paclitaxel-induced peripheral neuropathy

“…S2a and b). Consistent with previous studies1116, mice with paclitaxel treatment exhibited normal grip strength, compared to control groups (Fig. S2a and b).…”

“…Therefore, with the model of neurite outgrowth on DRG neurons, we first searched for potential neuroprotective agents by image-based high-content screening11. Paclitaxel was used as a neurotoxic drug to screen for potential neuroprotective agents from the compound libraries of ion channel ligands, REDOX and GABAergic ligands.…”

“…We then studied the protective mechanism of minoxidil on neuropathy. Previous studies have shown that paclitaxel dysregulates store-operated calcium entry (SOCE) that partly contributes the neurological pain1119. We used the DRG neuron cell line (ND7/23) to study the activation of SOCE in various conditions.…”

“…We have previously developed an image-based high-content platform which could be used to screen for potential neuroprotective drugs against paclitaxel neurotoxicity in cortical neurons11. This high-content screening system comprised of automated image acquisition and multiparameter analysis of neuronal functions.…”

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

“…In addition to causing a reduction in axonal Bclw mRNA and protein, we find that paclitaxel alters sensory neuron calcium dynamics, a critical component in pathological axon degeneration (Figure 6E) (Benbow et al, 2012; Bobylev et al, 2015; Boehmerle et al, 2007; Chen et al, 2015; Mo et al, 2012; Yilmaz and Gold, 2015). While it is well accepted that a rise in axonal calcium is necessary for calpain activation and for axon degeneration, the source and trigger of this calcium increase are not clear.…”