Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury

Abstract

Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The treatment of TBI in the acute phase has improved substantially; however, the prevention and management of long-term complications remain a challenge. Blood–brain barrier (BBB) breakdown has often been documented in patients with TBI, but the role of such vascular pathology in neurological dysfunction has only recently been explored. Animal studies have demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration. Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI and suggest that such pathology could be used as a biomarker in the clinic and in drug trials. Here, we review the neurological consequences of TBI, focusing on the long-term complications of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and examine the primary and secondary mechanisms that underlie such pathology. We go on to consider the consequences of BBB injury, before analyzing potential mechanisms linking vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for treatment. Finally, we highlight areas for future basic research and clinical studies into TBI.

Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

“…Intracranial consequences include mass lesions, focal/diffuse brain swelling, intracranial hypertension, seizures, vasospasm, or infection, whereas extracranial consequences include hypotension, hypoxia, hypercapnia/hypocapnia, hyperglycemia/hypoglycemia, anemia, pyrexia, electrolyte abnormalities, coagulopathy, and infection [4]. These secondary injuries from TBI lead to alterations in cell function and propagation of injury through processes such as depolarization, excitotoxicity, disruption of calcium homeostasis, free-radical generation, blood-brain barrier disruption, ischemic injury, edema formation, and intracranial hypertension [5][6][7]. Apart from prevention, little can be done to mitigate primary injury, whereas the "rolling" pathology of the delayed secondary injury allows therapeutic intervention within a window of limited time.…”

Osteoblasts Have a Neural Origin in Heterotopic Ossification

“…Recently it has become very obvious that there is a relationship between traumatic brain injury and HO [1,40]. One possible reason that HO is associated with traumatic brain injury, which causes a breakdown in the BBB [36,40], could be that changes in this barrier lead to the exit of these neural progenitors that can engraft and become osteoblasts, particularly at sites where BMP-2 may be present such as those that have also sustained an injury to bone, thus releasing BMP-2.…”

Neuroprotective roles of the P2Y2 receptor

“…Astrocytes are derived from the ectoderm and contribute to the maintenance of the bloodbrain barrier (BBB) [120][121][122], which prevents invasion of pathogenic substances into the brain from the circulation [123]. Astrocytes also release neurotrophic factors that play an important role in neuronal survival and sprouting and supply energy substrates to neurons [124].…”