Chronic cisplatin treatment in young mice induces long-term complications in the peripheral nervous system in a sex-dependent manner

Abstract

Cisplatin-induced peripheral neuropathy (CIPN) is one of the most prevalent long-term complications in pediatric cancer survivors reaching adulthood. However, very few studies have evaluated the long-term effects of cisplatin administered to the young population on the peripheral nervous system and assessed whether these effects are sex-dependent. Thus, we aimed to assess baseline mechanical withdrawal thresholds (a CIPN measurement), the density of CGRP⁺ and PGP9.5⁺ axons in the glabrous skin, changes in different markers in DRG, and determine pain-like responses after intra-plantar capsaicin in female and male mice at 4 weeks after cessation of cisplatin. Four-week-old BALB/c mice were treated with cisplatin (4 mg/kg, intraperitoneally, twice weekly for 4 weeks). Four weeks after cessation of cisplatin, these mice, at 12 weeks of age, exhibited significant hindpaw mechanical hypersensitivity, which was greater in magnitude in female mice compared to male mice. At 13 weeks old, cisplatin-treated mice also had a greater density of CGRP⁺ and PGP9.5⁺ intraepidermal nerve fibers compared to saline-treated groups in female and male mice, independent of sex. The number of CGRP⁺ and ATF3⁺ neuronal profiles and CD68⁺ monocyte/macrophage in L4 DRG was higher in cisplatin-treated mice than in saline-treated mice, independent of sex. Intra-plantar capsaicin injection in adult mice resulted in greater and longer flinching and guarding behaviors in cisplatin-pretreated mice compared to saline-pretreated mice. The enhanced capsaicin-induced pain behaviors were significantly greater in female compared to male mice. These findings demonstrate long-term, partially sex-related complications in the peripheral nervous system following cisplatin treatment.