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Paclitaxel is an antineoplastic drug extracted from the Taxus species, and peripheral neuropathy is a common side effect. Paclitaxel-induced peripheral neuropathy (PIPN) seriously affects patient quality of life. Currently, the mechanism of PIPN is still unknown, and few treatments are recognized clinically. Duloxetine is recommend as the only potential treatment for chemotherapy-induced peripheral neuropathy (CIPN) by the American Society of Clinical Oncology (ASCO). However, this guidance lacks a theoretical basis and experimental evidence. Our study suggested that duloxetine could improve PIPN and provide neuroprotection. We explored the potential mechanisms of duloxetine on PIPN. As a result, duloxetine acts by inhibiting PARP cleavage and p53 activation and regulating the Bcl2 family to reverse paclitaxel(PTX)-induced oxidative stress and apoptosis. Taken together, the present study shows that using duloxetine to attenuate PTX-induced peripheral nerve injury and peripheral pain may lead to new clinical targets for CIPN. SIGNIFICANCE STATEMENT: This study reported duloxetine markedly reduces neuropathic pain evoked by Paclitaxel (PTX), and related to PARP, p53 and the Bcl2 family. Our findings thus not only provide an important guidance to support duloxetine to become the first standard chemotherapy-induced peripheral neuropathy (CIPN) drug, but also will find potential new targets and positive control for new CIPN drug development.

Duloxetine Attenuates Paclitaxel-Induced Peripheral Nerve Injury by Inhibiting p53-Related Pathways