Figure 6: Yes1 inhibition mitigates Oct2-dependent oxaliplatin neurotoxicity.

(a) Wild-type FVB mice were injected with vehicle and the Oct1/2^−/− mice were injected with either vehicle or dasatinib (15 mg kg⁻¹, p.o.) and 30 min later, DRGs were collected. DRG lysates were then used to immunoprecipitate endogenous Oct2 followed by western blot analysis by phospho-tyrosine and Oct2 antibodies. (b) DRGs were collected from Wild-type and Yes1^−/− mice. The upper panel shows representative blots from experiments where DRG lysates were used to immunoprecipitate endogenous Oct2 followed by western blot analysis by phospho-tyrosine and Oct2 antibodies. The lower panel shows western blot results from total DRG lysates showing that Yes1 is expressed in DRGs in the wild-type mice. (c) DRGs were collected from Wild-type FVB mice, followed by satellite cell isolation and culture. The primary satellite cells were then plated in six-well plates followed by oxaliplatin uptake assays in the presence of DMSO, lapatinib or Dasatinib (30 min). The graph represents relative oxaliplatin uptake as compared to DMSO group. * indicates a statistically significant difference compared with the DMSO group. (d) Sensitivity to cold associated with a single dose of oxaliplatin (40 mg kg⁻¹) in wild-type mice pretreated with vehicle or dasatinib (15 mg kg⁻¹, p.o.) as determined by a cold-plate test. The number of paw lifts or licks at baseline and following exposure to a temperature of −4 °C for 5 min at 24 h after drug administration was determined (n=5). The graph represents relative percentage change in paw lifts/licks as compared with baseline values. (e) Mechanical allodynia associated with a single dose of oxaliplatin (40 mg kg⁻¹) in wild-type mice pretreated with vehicle or dasatinib (15 mg kg⁻¹, p.o.), as determined by a Von Frey Hairs test. The force required to induce paw withdrawal in grams (g) at baseline was measured following 24 h after drug administration (n=5). The graph represents relative percentage change in paw withdrawal force as compared to baseline values. * indicates a statistically significant difference as compared with the baseline (untreated) values. All experimental values are presented as mean±s.e.m. The height of error bar=1 s.e.