• Dennis W Simon, Rajesh K Aneja, Henry Alexander, Michael J Bell, Hülya Bayır, Patrick M Kochanek, and Clark Robert S B RSB 1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania. .
• 1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
• J. Neurotrauma. 2018 Jan 1; 35 (1): 130-138.

AbstractIn response to cell injury, the danger signal high mobility group box-1 (HMGB) is released, activating macrophages by binding pattern recognition receptors. We investigated the role of the anti-inflammatory drug minocycline in attenuating HMGB1 translocation, microglial activation, and neuronal injury in a rat model of pediatric traumatic brain injury (TBI). Post-natal day 17 Sprague-Dawley rats underwent moderate-severe controlled cortical impact (CCI). Animals were randomized to treatment with minocycline (90 mg/kg, intraperitoneally) or vehicle (saline) at 10 min and 20 h after injury. Shams received anesthesia and craniotomy. We analyzed HMGB1 translocation (protein fractionation and Western blotting), microglial activation (Iba-1 immunohistochemistry), neuronal death (Fluoro-Jade-B [FJB] immunofluorescence), and neuronal cell counts (unbiased stereology). Behavioral assessments included motor and Morris-water maze testing. Nuclear to cytosolic translocation of HMGB1 in the injured brain was attenuated in minocycline versus vehicle-treated rats at 24 h (p < 0.001). Treatment with minocycline reduced microglial activation in the ipsilateral cortex, hippocampus, and thalamus (p < 0.05 vs. vehicle, all regions); attenuated neurodegeneration (FJB-positive neurons) at seven days (p < 0.05 vs. vehicle); and increased thalamic neuronal survival at 14 days (naïve 22773 ± 1012 cells/mm3, CCI + vehicle 11753 ± 464, CCI + minocycline 17047 ± 524; p < 0.001). Minocycline-treated rats demonstrated delayed motor recovery early after injury but had no injury effect on Morris-water maze whereas vehicle-treated rats performed worse than sham on the final two days of testing (both p < 0.05 vs. vehicle). Minocycline globally attenuated HMGB1 translocation and microglial activation in injured brain in a pediatric TBI model and afforded selective thalamic neuroprotection. The HMGB1 translocation and thalamic injury may represent novel mechanistic and regional therapeutic targets in pediatric TBI.

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