Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging.

• Main Authors: Dawid Schellingerhout, Lucia G LeRoux, Brian P Hobbs, Sebastian Bredow
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2012-01-01
• Series: PLoS ONE
• Online Access: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23029238/?tool=EBI

<h4>Background and purpose</h4>The purpose of our study was to utilize a molecular imaging technology based on the retrograde axonal transport mechanism (neurography), to determine if oxaliplatin-induced neurotoxicity affects retrograde axonal transport in an animal model.<h4>Materials and methods</h4>Mice (n = 8/group) were injected with a cumulative dose of 30 mg/kg oxaliplatin (sufficient to induce neurotoxicity) or dextrose control injections. Intramuscular injections of Tetanus Toxin C-fragment (TTc) labeled with Alexa 790 fluorescent dye were done (15 ug/20 uL) in the left calf muscles, and in vivo fluorescent imaging performed (0-60 min) at baseline, and then weekly for 5 weeks, followed by 2-weekly imaging out to 9 weeks. Tissues were harvested for immunohistochemical analysis.<h4>Results</h4>With sham treatment, TTc transport causes fluorescent signal intensity over the thoracic spine to increase from 0 to 60 minutes after injection. On average, fluorescence signal increased 722%+/-117% (Mean+/-SD) from 0 to 60 minutes. Oxaliplatin treated animals had comparable transport at baseline (787%+/-140%), but transport rapidly decreased through the course of the study, falling to 363%+/-88%, 269%+/-96%, 191%+/-58%, 121%+/-39%, 75%+/-21% with each successive week and stabilizing around 57% (+/-15%) at 7 weeks. Statistically significant divergence occurred at approximately 3 weeks (p≤0.05, linear mixed-effects regression model). Quantitative immuno-fluorescence histology with a constant cutoff threshold showed reduced TTc in the spinal cord at 7 weeks for treated animals versus controls (5.2 Arbitrary Units +/-0.52 vs 7.1 AU +/-1.38, p<0.0004, T-test). There was no significant difference in neural cell mass between the two groups as shown with NeuN staining (10.2+/-1.21 vs 10.5 AU +/-1.53, p>0.56, T-test).<h4>Conclusion</h4>We show-for the first time to our knowledge-that neurographic in vivo molecular imaging can demonstrate imaging changes in a model of oxaliplatin-induced neuropathy. Impaired retrograde neural transport is suggested to be an important part of the pathophysiology of oxaliplatin-induced neuropathy.