Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy

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.
Using minoxidil as an initial template for structural modifications
in conjunction with an in vitro neurite outgrowth assay, an image-based
high-content screening platform, and mouse behavior models, an effective
neuroprotective agent CN016 was discovered. Our results showed that
CN016 could inhibit paclitaxel-induced inflammatory responses and
infiltration of immune cells into sensory neurons significantly. Thus,
the suppression of proinflammatory factors elucidates, in part, the
mechanism of action of CN016 on alleviating paclitaxel-induced peripheral
neuropathy. Based on excellent efficacy in improving behavioral functions,
high safety profiles (MTD > 500 mg/kg), and a large therapeutic
window
(MTD/MED > 50) in mice, CN016 might have great potential to become
a peripherally neuroprotective agent to prevent neurotoxicity caused
by chemotherapeutics as typified by paclitaxel.