Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

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...

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Autores principales:	Aysel Cetinkaya-Fisgin, Xinghua Luan, Nicole Reed, Ye Eun Jeong, Byoung Chol Oh, Ahmet Hoke
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/34702de21add40cd9739b7d7b3070316
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spelling	oai:doaj.org-article:34702de21add40cd9739b7d7b30703162021-12-02T12:42:28ZCisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation10.1038/s41598-020-78896-w2045-2322https://doaj.org/article/34702de21add40cd9739b7d7b30703162020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78896-whttps://doaj.org/toc/2045-2322Abstract 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.Aysel Cetinkaya-FisginXinghua LuanNicole ReedYe Eun JeongByoung Chol OhAhmet HokeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aysel Cetinkaya-Fisgin Xinghua Luan Nicole Reed Ye Eun Jeong Byoung Chol Oh Ahmet Hoke Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
description	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.
format	article
author	Aysel Cetinkaya-Fisgin Xinghua Luan Nicole Reed Ye Eun Jeong Byoung Chol Oh Ahmet Hoke
author_facet	Aysel Cetinkaya-Fisgin Xinghua Luan Nicole Reed Ye Eun Jeong Byoung Chol Oh Ahmet Hoke
author_sort	Aysel Cetinkaya-Fisgin
title	Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
title_short	Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
title_full	Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
title_fullStr	Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
title_full_unstemmed	Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
title_sort	cisplatin induced neurotoxicity is mediated by sarm1 and calpain activation
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/34702de21add40cd9739b7d7b3070316
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Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

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