Cisplatin Provokes Peripheral Nociception and Neuronal Features of Therapy-Induced Senescence and Calcium Dysregulation in Rats.

ABSTRACT

Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy-related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We here show that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-ß-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.