Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation.
Sci Rep
; 10(1): 21889, 2020 12 14.
Article
in En
| MEDLINE
| ID: mdl-33318563
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Calpain
/
Cisplatin
/
Neurotoxicity Syndromes
/
Cytoskeletal Proteins
/
Armadillo Domain Proteins
Limits:
Animals
Language:
En
Journal:
Sci Rep
Year:
2020
Document type:
Article
Affiliation country:
United States