Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity: Phenotypic and genotypic insights

Abstract

Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.

Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model

“…No significant differences were found between LT and HT animals regarding anxiety-like behavior (F [1,46] = 2190, n.s.). As previously shown, 5 in the D/L paradigm, we observed that SNI-L animals presented an increased anxiety-like behavior when compared with SNI-R animals (F [1,43] = 4.108, P < 0.05).…”

“…Independent of threshold, these parameters were statistically correlated (Pearson correlation = −0,480; P < 0.01; Figure 2C). SNI LT and SNI HT show no differences regarding lesion side comparison (F [1,46] = 0.002, n.s.). Later assessment, after the application of the battery of behavioral tests and the day before sacrifice, a similar pattern was observed for evoked (F [4,55] = 368.006, P < 0.001), spontaneous pain-like behaviors (F [4,55] = 3760, P < 0.01; Sham vs SNI LT …”

“…No side and no threshold effects were observed in baseline (F [1,46] = 0.140, n.s. Freezing in the last session was used as an index of fear contextual memory.…”

“…Freezing in the last session was used as an index of fear contextual memory. ( Figure 5A), CS (F [1,46] = 0.678, n.s. ); (F [1,46] = 0.611, n.s.)…”

“…effects in immobility time were observed. and threshold (F [1,46] = 1525, n.s.) and threshold (F [1,46] = 1525, n.s.)…”