Abstract 5260: Prevention of oxaliplatin-induced neuropathy by using minocycline as a chemoprotectant: demonstration by imaging and behavioral assessment

Abstract

Abstract Purpose: To utilize neurography, a novel imaging method based on retrograde transport of a molecular nerve imaging tracer, to assess the protective effect of minocycline on the development of Oxaliplatin-induced neuropathy. Materials and Methods: Female BALB/c mice received one of four treatments vehicle/vehicle, vehicle/minocycline, Oxaliplatin/vehicle, or Oxaliplatin/minocycline (n = 8/group). A 30 mg/kg cumulative dose of Oxaliplatin or dextrose vehicle was given in 10 divided intra-peritoneal doses across 3 weeks using two 5 days cycles. Animals were treated daily with 50 mg/kg minocycline or 0.9% saline vehicle by oral gavage beginning 48 h prior to the first Oxaliplatin treatment. Both imaging and behavioral data were collected at baseline and weekly for 3 weeks. For each imaging session, animals received fluorescently labeled TTc-Alexa790 (15 ug/20 uL) via intramuscular injection into the calf muscles. Fluorescent imaging (Xenogen IVIS 200) was used to image the distribution of TTc over 60 minutes, with ROI measurements taken over the lumbo-thoracic junction of the spine to quantitate fluorescent uptake. Neurobehavioral assessment for mechanical sensitivity was assessed through the use of von Frey nylon filaments to exert calibrated force on the footpads. The 50% hind paw withdrawal threshold was calculated. Results: Oxaliplatin/vehicle treated animals showed a significant decrease in transport of TTc during the second week of treatment (F (1,12) = 39.604, p<0.001), while the TTc transport of the vehicle/vehicle and oxaliplatin/minocycline remained stable across the experiment. The vehicle/minocycline group saw an increase in transport of TTc during the second week of treatments (F (1,12) = 42.533, p<0.001). Behavioral data indicated that Oxaliplatin treatment resulted in increased mechanical sensitivity, while minocycline treatment abrogated this effect, such that animals in the Oxaliplatin/vehicle group showed increased sensitivity compared to all other groups. This effect emerged within the first week of treatment and remained throughout the study. A linear correlation between paw withdrawal threshold and TTc transport at week 3 was found, with r = 0.7939, p<0.01, such that subjects with reduced TTc transport also displayed reduced mechanical thresholds. Conclusion: Oxaliplatin causes a decrease in retrograde axonal transport, and this reduction in transport correlates with neurobehavioral impairment due to neuropathy. We show that this effect can be attenuated by a chemo-protectant, minocycline, and that the protectant effect was apparent with both behavioral and imaging readouts. This suggests that minocycline can prevent the neuropathy induced by Oxaliplatin and that the mechanism of both the pathological effect and its prevention are related to retrograde axonal transport. Citation Format: Dawid Schellingerhout, Elizabeth Vichaya, Leo G. Flores, Daniela Ramos, Lucia Le Roux. Prevention of oxaliplatin-induced neuropathy by using minocycline as a chemoprotectant: demonstration by imaging and behavioral assessment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5260.