Effects of concussion on the blood–brain barrier in humans and rodents

Abstract

Traumatic brain injury and the long-term consequences of repeated concussions constitute mounting concerns in the United States, with 5.3 million individuals living with a traumatic brain injury-related disability. Attempts to understand mechanisms and possible therapeutic approaches to alleviate the consequences of repeat mild concussions or traumatic brain injury on cerebral vasculature depend on several aspects of the trauma, including: (1) the physical characteristics of trauma or insult that result in damage; (2) the time ''window'' after trauma in which neuropathological features develop; (3) methods to detect possible breakdown of the blood-brain barrier; and (4) understanding different consequences of a single concussion as compared with multiple concussions. We review the literature to summarize the current understanding of blood-brain barrier and endothelial cell changes post-neurotrauma in concussions and mild traumatic brain injury. Attention is focused on concussion and traumatic brain injury in humans, with a goal of pointing out the gaps in our knowledge and how studies of rodent model systems of concussion may help in filling these gaps. Specifically, we focus on disruptions that concussion causes to the blood-brain barrier and its multifaceted consequences. Importantly, the magnitude of post-concussion blood-brain barrier dysfunction may influence the time course and extent of neuronal recovery; hence, we include in this review comparisons of more severe traumatic brain injury to concussion where appropriate. Finally, we address the important, and still unresolved, issue of how best to detect possible breakdown in the blood-brain barrier following neurotrauma by exploring intravascular tracer injection in animal models to examine leakage into the brain parenchyma.

Distinguishing and phenotype monitoring of traumatic brain injury and post-concussion syndrome including chronic migraine in serum of Iraq and Afghanistan war veterans

“…More novel and specific biochemical/cellular pathway affects observed in this study include a potential blood brain barrier (BBB) phenotype in the TBI “most affected” vs control and in the TBI plus and minus CM comparisons (Table 3, Figs 6 and 7). These observations about BBB effects in the present TBI study are in line with a previous analysis concerning effects of concussion on the BBB in humans and in rats [68]. Notably, a depression phenotype was observed in the TBI “most affected” vs control comparison (Table 3, Fig 6), and a migraine headache phenotype was observed in the TBI plus vs minus CM comparison (Table 3 and Fig 7).…”

Traumatic Brain Injury and Blood–Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

“…The junctions between endothelial cells are tightly connected through the adherens junction (AJ) proteins such as cadherins and tight junctional proteins such as occludin and claudins [31]. Besides, astrocytes, microglia, and pericytes are also critical for the normal function of the BBB and the phenotype of brain endothelial cells so that they contribute to the formation and maintenance, selectivity, and specificity of the BBB [19,32]. Glial and endothelial cells functionally interact with each other in a paracrine manner contributing to the integrity of the BBB [30].…”

“…Needless to say that these post-traumatic effects burden the patient with a higher risk of re-hospitalization, as well as an additional economic burden for the individual and his/her family and reduced quality of life [17,18]. Researchers in the field have been focusing on several aspects of TBI, including the physical characteristics of the trauma and the lapse time between trauma and the initial onset of neuropathologies [19]. The development of TBI is divided into two general stages: primary (immediate) injury and secondary (delayed) injury [2,20].…”

BBB pathophysiology independent delivery of siRNA in traumatic brain injury

“…One approach to overcome BBB in TBI involves systemic administration of therapeutics while the BBB is physically breached post-injury (14)(15)(16). However, physical breaching of BBB in TBI is highly heterogeneous and varies greatly among patients, depending on the extent of primary injury (17)(18)(19)(20). Moreover, BBB can self-repair within a few hours to days post-injury to restore its integrity (16)(17)(18)(19)(20).…”