Blood–Brain Barrier Pathophysiology in Traumatic Brain Injury

Abstract

The blood-brain barrier (BBB) is formed by tightly connected cerebrovascular endothelial cells, but its normal function also depends on paracrine interactions between the brain endothelium and closely located glia. There is a growing consensus that brain injury, whether it is ischemic, hemorrhagic, or traumatic, leads to dysfunction of the BBB. Changes in BBB function observed after injury are thought to contribute to the loss of neural tissue and to affect the response to neuroprotective drugs. New discoveries suggest that considering the entire gliovascular unit, rather than the BBB alone, will expand our understanding of the cellular and molecular responses to traumatic brain injury (TBI). This review will address the BBB breakdown in TBI, the role of blood-borne factors in affecting the function of the gliovascular unit, changes in BBB permeability and post-traumatic edema formation, and the major pathophysiological factors associated with TBI that may contribute to post-traumatic dysfunction of the BBB. The key role of neuroinflammation and the possible effect of injury on transport mechanisms at the BBB will also be described. Finally, the potential role of the BBB as a target for therapeutic intervention through restoration of normal BBB function after injury and/or by harnessing the cerebrovascular endothelium to produce neurotrophic growth factors will be discussed.

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery

“…Median total symptoms and symptom severity were 7.5 (IQR 5 -13) and 12.0 (IQR 5.3 -22.6), respectively, at the time of medical evaluation. At the time of blood sampling, the median total symptoms reported by athletes with SRC was 5 (IQR 4-11), and the median symptom severity was 8 (IQR [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. At the time of blood sampling, compared to healthy controls, athletes with SRC had significantly higher total symptoms scores (median score = 5.0 vs. 3.0 respectively; p = 0.04, data not shown) but not symptom severity scores.…”

“…An important component of this is identifying how and why certain molecules appear in the peripheral blood after injury. This requires a greater understanding of mechanisms involved in glymphatic clearance (18,(55)(56)(57), BBB disruption, and neuroendocrine dysfunction (17,19,21). In view of the latter, injury-induced alterations to hormones produced by both the sympathetic nervous system and hypothalamic-pituitary-adrenal (HPA)-axis can modulate peripheral immune function, altering blood levels of cytokines and chemokines (58)(59)(60).…”

“…Multiple lines of evidence suggest that markers reflecting brain injury and repair may appear in the peripheral circulation through several mechanisms, including transport across a disrupted blood-brain barrier (BBB) (15)(16)(17), glymphatic clearance (18), or aberrant neuroendocrine signalling (19)(20)(21).…”

Application of High-Intensity Focused Ultrasound to the Study of Mild Traumatic Brain Injury

“…In their study of traumatic brain injury induced by controlled cortical impact, Myer et al (2006) concluded that reactive astrocytes play essential protective roles, by preserving neural tissue and restricting inflammation after moderate brain injury. In the present study, a single HIFU exposure was sufficient to elicit an elevation in GFAP immunostaining in astrocytes, a characteristic neuro-immune response to blood-brain barrier cellular injury or infection (Abbott et al 2010;Chodobski et al 2011;Wolburg et al 2009). In this study, the animals were followed for only 24 h; a longer survival time is needed to establish the profile of astroglial activation.…”

BBB-targeting, protein-based nanomedicines for drug and nucleic acid delivery to the CNS

“…This is followed by 161 two peaks of BBB opening at 4-6 hours and 2-3 days after the insult 162 (Chodobski et al 2011). Thus, though the extent and particular moments of 163 BBB permeability varies in the different pathologies, it can be used as a 164 therapeutic time-window to deliver molecules into the CNS (Rosenberg 2012).…”