The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced Drosophila Model of Peripheral Neuropathy

Biomedicines

Young-Yeon Kim¹  Kang-Min Lee¹  Jung-Eun Shin¹  Hye-Ji Jang¹  Jeanho Yun¹ 

[1] Peripheral Neuropathy Research Center, Dong-A University, Busan 49201, Korea;

关键词: peripheral neuropathy;    paclitaxel;    niclosamide;    PINK1;    mitochondrial dysfunction;   

DOI  :  10.3390/biomedicines10040863

来源: DOAJ

【 摘 要 】

Paclitaxel is a widely used anticancer drug that induces dose-limiting peripheral neuropathy. Mitochondrial dysfunction has been implicated in paclitaxel-induced neuronal damage and in the onset of peripheral neuropathy. We have previously shown that the expression of PINK1, a key mediator of mitochondrial quality control, ameliorated the paclitaxel-induced thermal hyperalgesia phenotype and restored mitochondrial homeostasis in Drosophila larvae. In this study, we show that the small-molecule PINK1 activator niclosamide exhibits therapeutic potential for paclitaxel-induced peripheral neuropathy. Specifically, niclosamide cotreatment significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae in a PINK1-dependent manner. Paclitaxel-induced alteration of the dendrite structure of class IV dendritic arborization (C4da) neurons was not reduced upon niclosamide treatment. In contrast, paclitaxel treatment-induced increases in both mitochondrial ROS and aberrant mitophagy levels in C4da neurons were significantly suppressed by niclosamide. In addition, niclosamide suppressed paclitaxel-induced mitochondrial dysfunction in human SH-SY5Y cells in a PINK1-dependent manner. These results suggest that niclosamide alleviates thermal hyperalgesia by attenuating paclitaxel-induced mitochondrial dysfunction. Taken together, our results suggest that niclosamide is a potential candidate for the treatment of paclitaxel-induced peripheral neuropathy with low toxicity in neurons and that targeting mitochondrial dysfunction is a promising strategy for the treatment of chemotherapy-induced peripheral neuropathy.

【 授权许可】

Unknown