Impact of Dose, Sex, and Strain on Oxaliplatin-Induced Peripheral Neuropathy in Mice

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose limiting, and long-lasting side effect of chemotherapy treatment. Unfortunately, no treatment has proven efficacious for this side effect. Rodent models play a crucial role in the discovery of new mechanisms underlying the initiation, progression, and recovery of CIPN and the potential discovery of new therapeutics. However, there is limited consistency in the dose, the sex, age, and genetic background of the animal used in these studies and the outcome measures used in evaluation of CIPN rely primarily on noxious and reflexive measures. The main objective of this study was to provide a comprehensive and systematic characterization of oxaliplatin-induced peripheral neuropathy in mice by using a battery of behavioral, sensory, electrophysiological, and morphometric measures in both sexes of the two widely used strains of mice, C57BL/6J and BALB/cJ. Mice received intraperitoneal injections of 3 or 30 mg/kg cumulative doses of oxaliplatin over the course of 2 weeks. Both doses induced long-term and time-dependent mechanical and cold hypersensitivity. Our results show that 30 mg/kg oxaliplatin reduced the locomotor activity in C57BL/6J mice, and C57BL/6J females showed anxiety-like behavior one-week post completion of treatment. In the same dose group, BALB/cJ males and females sustained a larger decrease in sucrose preference than either male or female C57BL/6J mice. Both strains failed to show significant changes in burrowing and nesting behaviors. Two clinically relevant assessments of changes to the peripheral nerve fibers, nerve conduction and intraepidermal nerve fiber density (IENFD) were evaluated. Only BALB/cJ females showed significant reduction in the nerve conduction amplitude 1 week after 30 mg/kg oxaliplatin regimen. Moreover, this dose of the chemo agent reduced the IENF density in both sexes and strains. Our findings suggest that mouse strain, sex, and assay type should be carefully considered when assessing the effects of oxaliplatin and potential therapeutic interventions.

Loss of GABA co-transmission from cholinergic neurons impairs behaviors related to hippocampal, striatal, and medial prefrontal cortex functions

“…We observed increased locomotion in male CKO mice only in the 3-chamber test and the automated home-cage assay. Consistent with the literature, however, female ctrl mice were generally more active than male ctrl mice in the automated home-cage assay (Caldarone et al (2008), Rosenfeld (2017), Holcomb et al (2022), Warncke et al (2021), Stevanovic et al (2022)). Changes in locomotion have been reported in drug abuse models, in response to disturbed striatal DA transport and receptor function, and in patients with bipolar disorders or schizophrenia potentially through ventral striatum nAChR signaling (Moy et al (2013), Singer et al (2012), Perry et al (2009), Moreno et al (2013), DeLong and Wichmann (2015), Amitai et al (2014), Jerlhag et al (2006)).…”

“…We observed increased locomotion in male CKO mice only in the 3-chamber test and the automated home-cage assay. Consistent with the literature, however, female ctrl mice were generally more active than male ctrl mice in the automated home-cage assay (Caldarone et al (2008), Rosenfeld (2017), Holcomb et al (2022, Warncke et al (2021), Stevanovic et al (2022)).…”

“…2008),Rosenfeld (2017),Holcomb et al (2022),Warncke et al (2021),Stevanovic et al (2022)). Changes in locomotion have been reported in drug abuse models, in response to disturbed striatal DA transport and receptor function, and in patients with bipolar disorders or schizophrenia potentially through ventral striatum nAChR signaling(Moy et al (2013),Singer et al (2012),Perry et al (2009),Moreno et al (2013),DeLong and Wichmann (2015),Amitai et al (2014),Jerlhag et al (2006)).…”

Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy

“…Potential limitations of our study are the relatively low number of patients and the confinement to gynecological tumors and therefore women. Although some sex-related differences were found in pain perception in CIPN in preclinical studies in mice, mainly regarding cold and mechanical hypersensitivity ( 29 , 30 ), severity of CIPN in electrophysiological studies was similar across strains and sex ( 30 ). Some clinical studies also indicate that the prevalence and severity of CIPN are not majorly different between the sexes ( 31 ).…”

Gender and Sex-Related Differences in Normal Tissue Effects Induced by Platinum Compounds

“…Studies investigating sex-dependent differences in normal tissue toxicity after treatment with platinum compounds other than cisplatin are scarce. A recent pre-clinical investigation using rodent models aimed to determine the impact of dose, sex, and strain on oxaliplatin-caused peripheral neuropathy [56]. The study was prompted by the lack of efficient therapies to overcome long-term platinum-induced peripheral neuropathy, one of the most common toxicities reported in the clinics.…”