Time Course and Size of Blood–Brain Barrier Opening in a Mouse Model of Blast-Induced Traumatic Brain Injury

Abstract

An increasing number of studies have reported blood-brain barrier (BBB) dysfunction after blast-induced traumatic brain injury (bTBI). Despite this evidence, there is limited quantitative understanding of the extent of BBB opening and the time course of damage after blast injury. In addition, many studies do not report kinematic parameters of head motion, making it difficult to separate contributions of primary and tertiary blast-loading. Detailed characterization of blast-induced BBB damage may hold important implications for serum constituents that may potentially cross the compromised barrier and contribute to neurotoxicity, neuroinflammation, and persistent neurologic deficits. Using an in vivo bTBI model, systemic administration of sodium fluorescein (NaFl; 376 Da), Evans blue (EB; 69 kDa when bound to serum albumin), and dextrans (3-500 kDa) was used to estimate the pore size of BBB opening and the time required for recovery. Exposure to blast with 272 ± 6 kPa peak overpressure, 0.69 ± 0.01 ms duration, and 65 ± 1 kPa*ms impulse resulted in significant acute extravasation of NaFl, 3 kDa dextran, and EB. However, there was no significant acute extravasation of 70 kDa or 500 kDa dextrans, and minimal to no extravasation of NaFl, dextrans, or EB 1 day after exposure. This study presents a detailed analysis of the time course and pore size of BBB opening after bTBI, supported by a characterization of kinematic parameters associated with blast-induced head motion.

Effects of Exposure to Blast Overpressure on Intracranial Pressure and Blood-Brain Barrier Permeability in a Rat Model

“…Consistent with previous studies, our results suggested EB fluorescence surrounding ventricle and corpus callosum may be associated with blast-induced direct vascular damage. Confocal images have shown strong widespread EB fluorescence in cortex after blast [14] and the optical density of EB in frontal cortex of blast group was over 60% higher than the sham group [11]. It was reported that focal lesions were present in many brain regions including the cortex, which were likely caused by direct shear effects induced by blast [31, 32].…”

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

“…Breakdown of the BBB after blast exposure is commonly reported (Elder et al, 2015; Kabu et al, 2015; Readnower et al, 2010; Shetty et al, 2014; Yeoh et al, 2013). We recently found significant changes in BBB integrity following primary blast loading in vitro and in vivo (Hue et al, 2014; Hue et al, 2013; Hue et al, 2015). Unlike the in vitro preparations, even a very small compromise of the blood-brain barrier could lead to serum components leaking into the extracellular space and triggering a strong gliotic response.…”

“…1B, C) designed with past work as reference: 1) mild blast - peak incident overpressure of 215 ± 13 kPa, duration of 0.65 ± 0.04 ms, and an impulse of 46 ± 5 kPa * ms, which is within the range of conditions causing cognitive impairment in rodents following blast exposure (Kovacs et al, 2014), and 2) moderate blast - peak incident overpressure of 415 ± 41 kPa, duration of 1.04 ± 0.04 ms, and impulse of 148 ± 12 kPa * ms, which is above the threshold for changes in BBB permeability in vitro (Hue et al, 2013; Hue et al, 2015) and LTP deficits in organotypic slice cultures (Effgen et al, 2014; Vogel et al, 2015). This range of blast loading is comparable to exposure to a 105-mm artillery round at a standoff distance of 5–10 m. The effects of unconstrained motion were only examined at the lower exposure level, as the higher exposure resulted in significant mortality.…”

Acute vitreoretinal trauma and inflammation after traumatic brain injury in mice

“…We did see BBB damage 24 h post LFPI, demonstrated by the immunohistochemical staining of mouse IgG at the injury site; additionally, a loss of BBB integrity using the bTBI model occurring within the 24 h post injury has been previously well established 23, 39. There was no visible disruption of the brain architecture at 24 days post blast injury.…”

“…There was no visible disruption of the brain architecture at 24 days post blast injury. It has been well documented that the integrity of BBB is reestablished 24 h post blast injury,23, 39but we wanted to verify that overt tissue disruption did not occur. Damage to the BBB in both of these models leads to the loss of the brain's normal immunologic privilege and isolation from the systemic immune system.…”