Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPAR activation

Background: Chemotherapy-induced peripheral neuropathy (CIPN) reduces the overall quality of life and leads to interruption of chemotherapy. Ursolic acid, a triterpenoid naturally which presents in fruit peels and in many herbs and spices, can function as a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, and has been widely used as an herbal medicine with a wide spectrum of pharmacological activities, including anti-cancer, anti-inflammatory and neuroprotective effect. Methods: We used a phenotypic drug screening approach to identify ursolic acid as a potential neuroprotective drug in vitro and in vivo and carried out additional biochemical experiments to identify its mechanism of action. Results: Our study demonstrated that ursolic acid reduced neurotoxicity and cell apoptosis induced by pacilitaxel, resulting in an improvement of CIPN. Moreover, we explored the potential mechanisms of ursolic acid on CIPN. As a result, ursolic acid inhibited CHOP (C/EBP Homologous Protein) expression, indicating the endoplasmic reticulum (ER) stress suppression, and regulating CHOP related apoptosis regulator (the Bcl2 family) to reverse pacilitaxel induced apoptosis. Moreover, we showed that the therapeutic effect of ursolic acid on the pacilitaxelinduced peripheral neuropathy is PPAR gamma dependent. Conclusions: Taken together, the present study suggests ursolic acid has potential as a new PPAR gamma agonist targeting ER stress-related apoptotic pathways to ameliorate pacilitaxel-induced peripheral neuropathic pain and nerve injury, providing new clinical therapeutic method for CIPN.