Abstract
BACKGROUND: Brain injury progression after severe traumatic brain injury (TBI) is associated with worsening cerebral inflammation but it is unknown how a concomitant bone fracture (BF) affects this progression. Enoxaparin (ENX) decreases penumbral leukocyte mobilization after TBI and improves neurologic recovery. We hypothesized that a concomitant BF worsens learning/memory recovery weeks after TBI and that ENX improves this recovery. METHODS: CD1 male mice underwent controlled cortical impact or sham craniotomy with or without tibial fracture, receiving either daily ENX (0.8 mg/kg) or saline for 14 days after injury. Randomization defined four groups (Sham, TBI only, TBI + Fx, TBI + Fx + ENX, n = 5/each). Body weight loss and neurologic recovery (Garcia Neurologic Test, max score = 18) were assessed each day. Mouse learning (swimming time [s] and total distance [m] to reach the submerged platform Days 14 to 17 after TBI) and memory (swimming time [s] in platform quadrant after platform removed [probe]) was assessed by the Morris water maze. Ly-6G (cerebral neutrophil sequestration) and glial fibrillary acidic protein were evaluated by immunohistochemistry in brain tissue post mortem. Analysis of variance with Tukey's post hoc test determined significance (p < 0.05). RESULTS: A concurrent BF worsened Garcia Neurologic Test scores post-TBI Days 2 to 4 (p < 0.01) as compared with TBI only, and ENX reversed this worsening on Day 4 (p < 0.01). Learning was significantly slower (greater swimming time and distance) in TBI + Fx versus TBI only on Day 17 (p < 0.01). This was despite similar swimming velocities in both groups, indicating intact extremity motor function. Memory was similar in isolated TBI and Sham which was significantly better than in TBI + Fx animals (p < 0.05). Glial fibrillary acidic protein-positive cells in penumbral cortex were most prevalent in TBI + Fx animals, significantly greater than in Sham (p < 0.05). CONCLUSION: A long BF accompanying TBI worsens early neurologic recovery and subsequent learning/memory. Enoxaparin may partially counter this and improve neurologic recovery.