Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
Open Access
- 14 December 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 10 (1), 1-12
- https://doi.org/10.1038/s41598-020-78896-w
Abstract
Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.Funding Information
- National Institute of Neurological Disorders and Stroke (R01 NS091260)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (119309)
This publication has 31 references indexed in Scilit:
- Chemotherapy‐induced peripheral neuropathy: A current reviewAnnals of Neurology, 2017
- Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in miceBrain, 2016
- Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicityScientific Reports, 2016
- Ethoxyquin prevents chemotherapy‐induced neurotoxicity via Hsp90 modulationAnnals of Neurology, 2013
- Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axonNeurobiology of Disease, 2013
- dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death PathwayScience, 2012
- Chemotherapy-Induced Peripheral Neuropathy: Prevention and TreatmentClinical Pharmacology & Therapeutics, 2011
- Erythropoietin protects sensory axons against paclitaxel-induced distal degenerationNeurobiology of Disease, 2006
- Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle.JCI Insight, 1998
- Incidence of neuropathy in 395 patients with ovarian cancer treated with or without cisplatinCancer, 1990