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Integrating Image-Based High-Content Screening with Mouse Models Identifies 5-Hydroxydecanoate as a Neuroprotective
Li-Hsien Chen1, Yuan-Ting Sun2, Yih-Fung Chen3
1Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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.
Insights
This study identified 5-hydroxydecanoate (5-HD) as a potential neuroprotective drug against chemotherapy-induced neurotoxicity. 5-HD effectively protected neurons and alleviated symptoms in mice without compromising cancer treatment efficacy.
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- Chemotherapy-induced neurotoxicity is a significant challenge in cancer care.
- Current treatments lack effective neuroprotective agents.
- Paclitaxel-induced neurotoxicity affects neuronal function and patient quality of life.
Purpose of the Study:
- To discover novel neuroprotective drugs for paclitaxel-induced neurotoxicity.
- To establish and validate an image-based high-content screening platform for neuroprotection.
- To investigate the therapeutic potential of 5-hydroxydecanoate (5-HD).
Main Methods:
- Developed an image-based high-content screening platform for neuronal viability, neurite outgrowth, and synaptogenesis.
- Screened compound libraries including ion channel ligands, REDOX, and GABAergic ligands.
- Validated 5-HD's efficacy in vitro (cortical and DRG neurons) and in vivo (mouse behavioral tests and sciatic nerve analysis).
- Investigated the mechanism involving intracellular calcium homeostasis.
- Assessed 5-HD's impact on paclitaxel's antitumor effect in xenograft models.
Main Results:
- 5-hydroxydecanoate (5-HD) demonstrated significant neuroprotective effects against paclitaxel-induced neurotoxicity in neuronal cultures.
- In vivo studies showed 5-HD restored thermal sensitivity and alleviated mechanical allodynia in paclitaxel-treated mice.
- 5-HD reduced sciatic nerve damage and normalized intracellular calcium dysregulation.
- Crucially, 5-HD did not interfere with paclitaxel's anticancer activity.
Conclusions:
- An effective image-based high-content screening platform for neuroprotection was established.
- 5-hydroxydecanoate (5-HD) is identified as a promising therapeutic agent for paclitaxel-induced neuropathy.
- 5-HD offers a potential strategy to mitigate chemotherapy side effects without compromising treatment efficacy.
