Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

• Published in: Scientific reports 2020-12, Vol.10 (1), p.21889-12, Article 21889
• Main Authors: Cetinkaya-Fisgin, Aysel, Luan, Xinghua, Reed, Nicole, Jeong, Ye Eun, Oh, Byoung Chol, Hoke, Ahmet
• Format: Article
• Language: English
• Subjects: 631/378/1687; 631/378/1959; Adducts; Animals; Armadillo Domain Proteins - genetics; Armadillo Domain Proteins - metabolism; Calpain; Calpain - genetics; Calpain - metabolism; Cells, Cultured; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - pharmacology; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA adducts; Enzyme Activation - drug effects; Enzyme Activation - genetics; Humanities and Social Sciences; Mice; Mice, Knockout; multidisciplinary; Neurodegeneration; Neurotoxicity; Neurotoxicity Syndromes - genetics; Neurotoxicity Syndromes - metabolism; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - genetics; Peripheral Nervous System Diseases - metabolism; Peripheral neuropathy; Platinum; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); Wallerian Degeneration - chemically induced; Wallerian Degeneration - genetics; Wallerian Degeneration - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-78896-w

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.