The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral Neuropathy
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 mitoch...
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MDPI AG
2022-04-01
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| Online Access: | https://www.mdpi.com/2227-9059/10/4/863 |
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| author | Hye-Ji Jang Young-Yeon Kim Kang-Min Lee Jung-Eun Shin Jeanho Yun |
| author_facet | Hye-Ji Jang Young-Yeon Kim Kang-Min Lee Jung-Eun Shin Jeanho Yun |
| author_sort | Hye-Ji Jang |
| collection | DOAJ |
| description | 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 <i>Drosophila</i> 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 <i>Drosophila</i> 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. |
| first_indexed | 2024-03-09T11:07:33Z |
| format | Article |
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| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T11:07:33Z |
| publishDate | 2022-04-01 |
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| series | Biomedicines |
| spelling | doaj.art-d52145fba6bf43d6bbc3ad8ab56d970a2023-12-01T00:54:31ZengMDPI AGBiomedicines2227-90592022-04-0110486310.3390/biomedicines10040863The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral NeuropathyHye-Ji Jang0Young-Yeon Kim1Kang-Min Lee2Jung-Eun Shin3Jeanho Yun4Peripheral Neuropathy Research Center, Dong-A University, Busan 49201, KoreaPeripheral Neuropathy Research Center, Dong-A University, Busan 49201, KoreaPeripheral Neuropathy Research Center, Dong-A University, Busan 49201, KoreaPeripheral Neuropathy Research Center, Dong-A University, Busan 49201, KoreaPeripheral Neuropathy Research Center, Dong-A University, Busan 49201, KoreaPaclitaxel 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 <i>Drosophila</i> 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 <i>Drosophila</i> 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.https://www.mdpi.com/2227-9059/10/4/863peripheral neuropathypaclitaxelniclosamidePINK1mitochondrial dysfunction |
| spellingShingle | Hye-Ji Jang Young-Yeon Kim Kang-Min Lee Jung-Eun Shin Jeanho Yun The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral Neuropathy Biomedicines peripheral neuropathy paclitaxel niclosamide PINK1 mitochondrial dysfunction |
| title | The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral Neuropathy |
| title_full | The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral Neuropathy |
| title_fullStr | The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral Neuropathy |
| title_full_unstemmed | The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral Neuropathy |
| title_short | The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced <i>Drosophila</i> Model of Peripheral Neuropathy |
| title_sort | pink1 activator niclosamide mitigates mitochondrial dysfunction and thermal hypersensitivity in a paclitaxel induced i drosophila i model of peripheral neuropathy |
| topic | peripheral neuropathy paclitaxel niclosamide PINK1 mitochondrial dysfunction |
| url | https://www.mdpi.com/2227-9059/10/4/863 |
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