Citation

Suto Y, Nagata K, Ahmed S, Jacovides C, Browne KD, Cognetti J, Johnson VE, Leone R, Kaplan LJ, Smith DH, Pascual JL. J. Neurotrauma 2019; 36(4): 609-618.

Affiliation

Univ Penn , 3400 Spruce St , Philadelphia , Pennsylvania, United States , 19104 ; Jose.pascual@uphs.upenn.edu.

Copyright

(Copyright © 2019, Mary Ann Liebert Publishers)

DOI

10.1089/neu.2018.5812

PMID

30084745

Abstract

Progression of severe TBI is associated with worsening cerebral inflammation but it is unknown how a concomitant bone fracture (FX) affects this progression. Enoxaparin (ENX), a low molecular weight heparin often used for venous thromboembolic prophylaxis, decreases penumbral leukocyte (LEU) mobilization in isolated TBI and improves neurological recovery. We investigated if TBI accompanied by a FX worsens leukocyte mediated cerebral inflammation and if ENX alters this process. CD1 male mice underwent controlled cortical impact (CCI) or sham craniotomy with or without an open tibial fracture, and received either ENX (1mg/kg, 3 times/day) or saline for 2 days following injury. Randomization defined 4 groups (Sham, CCI, CCI+FX, CCI+FX+ENX, n=10/group). Two days after CCI, neurological recovery was assessed with the Garcia Neurological Test (GNT); intravital microscopy (LEU rolling and adhesion, microvascular leakage) and blood hemoglobin levels were also evaluated. Penumbral cerebral neutrophil sequestration (Ly-6G immunohistochemistry- IHC) were evaluated post-mortem. In vivo LEU rolling was greater in CCI+FX (45.2±4.8 LEUs/100µm/min) than in CCI alone (26.5±3.1, p=0.007), and was suppressed by ENX (23.2±5.5, p=0.003 vs CCI+FX). Neurovascular permeability was higher in CCI+FX (71.1+/-2.9%) than CCI alone (42.5+/-2.3, p<0.001). GNT scores were lowest in CCI+FX (15.2±0.2) vs. CCI alone (16.3±0.3, p<0.001). Hemoglobin was lowest in the CCI+FX+ENX vs. Sham or CCI alone. IHC demonstrated greatest PMN invasion in CCI+FX in uninjured cerebral territories. A concomitant long bone fracture worsens TBI-induced cerebral leukocyte mobilization, microvascular leakage and cerebral edema, and impairs neurological recovery at 48 hours. ENX suppresses this progression but may increase bleeding.

Language: en

Keywords

BLOOD-BRAIN BARRIER DYSFUNCTION; Brain Edema; IN VIVO STUDIES; TRAUMATIC BRAIN INJURY; controlled cortical impact