title: Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Dawid.schellingerhout@mdanderson.org
authors.forename: Dawid
authors.initials: D
authors.lastname: Schellingerhout
authors.forename: Lucia G
authors.initials: LG
authors.lastname: LeRoux
authors.forename: Brian P
authors.initials: BP
authors.lastname: Hobbs
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bredow
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001692:Biological Transport; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010446:Peptide Fragments / Q000493:pharmacokinetics; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013744:Tetanus Toxin / Q000493:pharmacokinetics; D013904:Thoracic Vertebrae / Q000378:metabolism / Q000473:pathology; D051598:Whole Body Imaging
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D009944:Organoplatinum Compounds; D010446:Peptide Fragments; D013744:Tetanus Toxin; C549316:tetanus toxin (947-966); D000077150:Oxaliplatin