Mechanical disruption of the blood–brain barrier following experimental concussion

Abstract

Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood-brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6-72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray-white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion.

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…1) can occur as a result of the initial injury or arise secondarily to the extensive neuroinflammation, astrocytic dysfunction, and metabolic disturbances. These damages result in vascular leakage, brain edema, cerebral hemorrhage, and hypoxia [27,29,[33][34][35]. Neuronal apoptosis also significantly contributes to secondary injury [36,37].…”

A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

“…Unlike other widely used models, porcine subjects are particularly well suited as a pre-clinical model because the nerves are remarkably similar to humans. 33 Moreover, the similar physiology between humans and porcine have resulted in its increasing popularity as a preclinical translational research model in various areas, such as traumatic brain injury, [34][35][36][37][38][39][40] spinal cord injury, 41 wound healing, 42 cartilage repair, [43][44][45][46][47] intervertebral disc herniation, 48 coronary artery injury, 49 and gastrointestinal, 50 and hepatic surgery. 51 Indeed, the objective in the development of the porcine model presented in this study was to replicate critical features of extremely challenging repair and regeneration scenarios following major PNI in human.…”

Multichannel Silicon Probes for Awake Hippocampal Recordings in Large Animals

“…At the study endpoint, transcardial perfusion was performed under anesthesia using 0.9% heparinized saline followed by 10 % neutral buffered formalin (NBF). After further post-fixation for 7 days in 10 % NBF at 4 ° C, the brain was dissected into 5 mm blocks in the coronal plane and processed to paraffin using standard techniques [31,32]. 8 µm sections were obtained at the level of the hippocampus in and standard hematoxylin & eosin (H & E) staining was performed on all animals to identify electrode tracks.…”

“…After further rinsing, slides were differentiated in 95 % ethanol with 0.001 % acetic acid, followed by dehydration, clearing in xylenes and cover slipping using cytoseal-60. Immunohistochemistry (IHC): IHC labeling was performed according to previously published protocols [31][32][33] . Briefly, tissue sections were dewaxed and rehydrated as above, followed by immersion in 3 % aqueous hydrogen peroxide for 15 minutes to quench endogenous peroxidase activity.…”