Cisplatin-induced peripheral neuropathy is associated with neuronal senescence-like response
Neuro-Oncology, ISSN: 1523-5866, Vol: 23, Issue: 1, Page: 88-99
2021
- 38Citations
- 72Captures
- 1Mentions
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Metrics Details
- Citations38
- Citation Indexes38
- 38
- CrossRef35
- Captures72
- Readers72
- 72
- Mentions1
- News Mentions1
- 1
Most Recent News
Researchers identify the cellular process by which Cisplatin chemotherapy causes neuronal damage
Despite the great advances in cancer research in recent years, treatments that can cause very severe adverse effects are still used. This is the case of neuropathy caused by chemotherapy with platinum derivatives, such as Cisplatin and Oxaliplatin. These are widely used drugs that can damage the peripheral nervous system causing a progressive and increasing loss of sensitivity, which may even affe
Article Description
Background: Cisplatin-induced peripheral neuropathy (CIPN) is a frequent serious dose-dependent adverse event that can determine dosage limitations for cancer treatment. CIPN severity correlates with the amount of platinum detected in sensory neurons of the dorsal root ganglia (DRG). However, the exact pathophysiology of CIPN is poorly understood, so the chance of developing neuroprotective treatment is reduced. The aim of this study was to determine the exact mechanisms involved in CIPN development. Methods: By single-cell RNA-sequencing (scRNAseq), we have studied the transcriptomic profile of DRG sensory neurons from a well-characterized neurophysiological mouse model of CIPN. Results: Gene Ontology analysis of the scRNAseq data indicated that cisplatin treatment induces the upregulation of biological pathways related to DNA damage response (DDR) in the DRG neuronal population. Moreover, DRG neurons also upregulated the Cdkn1a gene, confirmed later by the measurement of its protein product p21. While apoptosis activation pathways were not observed in DRG sensory neurons of cisplatin-treated mice, these neurons did express several senescence hallmarks, including senescence-associated β-galactosidase, phospho-H2AX, and nuclear factor kappa B (Nfkb)-p65 proteins. Conclusions: In this study, we determined that after cisplatin-induced DNA damage, p21 appears as the most relevant downstream factor of the DDR in DRG sensory neurons in vivo, which survive in a nonfunctional senescence-like state.
Bibliographic Details
Oxford University Press (OUP)
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