Establishment of a Neurodegenerative Charcot Mouse Model.

Abstract

This study aimed to mimic the changes from Charcot neuropathic arthropathy in humans by examining the effects of exposing diet-induced obese (DIO) mice to neurotrauma through a regimented running protocol. Forty-eight male wild-type C57BL/6J mice were obtained at age 6 weeks and separated into 2 groups for diet assignment. After a 1-week acclimation period, half of the mice consumed a high-fat diet (60% fat by kcal) ad libitum to facilitate neuropathic diet-induced obesity whereas the other half were control mice and consumed an age-matched standard low-fat control diet (10% fat by kcal). At age 12 weeks, half of the animals from each group were subjected to a high-intensity inclined treadmill running protocol, which has been previously demonstrated to induce neurotrauma. Sensory testing and radiographic analyses were periodically performed. Histopathologic analyses were performed post killing. DIO mice had significantly higher bodyweights, higher body fat percentages, and lower bone mineral density than wildtype control mice that were fed a normal diet throughout the experiment (P < .001 for each). DIO mice displayed significantly reduced sensory function in week 1 (P = .005) and this worsened over time, requiring 20.6% more force for paw withdrawal by week 10 (P < .001). DIO mice that ran demonstrated greater midfoot subluxation and tarsal instability over all time points compared with normal-diet mice that ran (P < .001). Histopathologic analyses revealed that DIO mice that ran demonstrated significant changes compared with controls that ran (P < .001 for each parameter). Changes akin to the earliest changes observed in or before joint destruction identified in diabetic Charcot neuropathic arthropathy in humans were observed. There is currently no standard of treatment for patients with Charcot neuropathic arthropathy. This study establishes a protocol for an animal model that can be used to study and compare interventions to treat this disease.