Breakdown of the Blood–Brain Barrier after Fluid Percussive Brain Injury in the Rat. Part 1: Distribution and Time Course of Protein Extravasation

We have previously developed a model of mild, lateral fluid percussive head injury in the rat and demonstrated that although this injury produced minimal hemorrhage, breakdown of the blood–brain barrier was a prominent feature. The relationship between posttraumatic blood–brain barrier disruption and cellular injury is unclear. In the present study we examined the distribution and time course of expression of the stress protein HSP72 after brain injury and compared these findings with the known pattern of breakdown of the blood–brain barrier after a similar injury. Rats were subjected to a lateral fluid percussive brain injury (4.8–5.2 atm, 20 ms) and killed at 1, 3, and 6 h and 1,3, and 7 days after injury. HSP72-like immunoreactivity was evaluated in sections of brain at the light-microscopic level. The earliest expression of HSP72 occurred at 3 h postinjury and was restricted to neurons and glia in the cortex surrounding a necrotic area at the impact site. By 6 h, light immunostaining was also noted in the pia-arachnoid adjacent to the impact site and in certain blood vessels that coursed through the area of necrosis. Maximal immunostaining was observed by 24 h postinjury, and was primarily associated with the cortex immediately adjacent to the region of necrosis at the impact site. This region consisted of darkly immunostained neurons, glia, and blood vessels. Immunostaining within the region of necrosis was restricted to blood vessels. HSP72-like immunoreactivity was also noted in a limited number of neurons and glia in other brain regions, including the parasagittal cortex, deep cortical layer VI, and CA3 in the posterior hippocampus. Immunoreactive cells in these areas were not apparent until 24 h postinjury. By 7 days postinjury, HSP72-like immunoreactivity was minimal or absent in these injured brains and notable cell loss was apparent only in the impact site. This study demonstrates an early and pronounced expression of HSP72 at the impact site and a more delayed and less prominent expression of this protein in other regions of the brain. These findings parallel the temporal and regional pattern of breakdown of the blood–brain barrier after a similar head injury.

Download Full-text

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

Journal of Concussion ◽

10.1177/2059700216684518 ◽

2017 ◽

Vol 1 ◽

pp. 205970021668451 ◽

Cited By ~ 7

Author(s):

Ronald Sahyouni ◽

Paula Gutierrez ◽

Eric Gold ◽

Richard T Robertson ◽

Brian J Cummings

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Blood Brain Barrier ◽

Time Course ◽

Time Window ◽

The United States ◽

Model Systems ◽

Brain Barrier ◽

Tracer Injection ◽

Blood Brain

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.

Download Full-text

Blood-brain barrier dysfunction significantly correlates with serum matrix metalloproteinase-7 (MMP-7) following traumatic brain injury

NeuroImage Clinical ◽

10.1016/j.nicl.2021.102741 ◽

2021 ◽

pp. 102741

Author(s):

Paul Nichols ◽

Javier Urriola ◽

Stephanie Miller ◽

Tracey Bjorkman ◽

Kate Mahady ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Matrix Metalloproteinase ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Matrix Metalloproteinase 7

Download Full-text

ELEVATION OF MATRIX METALLOPROTEINASES 3 AND 9 IN CEREBROSPINAL FLUID AND BLOOD IN PATIENTS WITH SEVERE TRAUMATIC BRAIN INJURY

Neurosurgery ◽

10.1227/01.neu.0000351768.11363.48 ◽

2009 ◽

Vol 65 (4) ◽

pp. 702-708 ◽

Cited By ~ 95

Author(s):

Mark Grossetete ◽

Jeremy Phelps ◽

Leopold Arko ◽

Howard Yonas ◽

Gary A. Rosenberg

Keyword(s):

Traumatic Brain Injury ◽

Cerebrospinal Fluid ◽

Brain Injury ◽

Matrix Metalloproteinases ◽

Blood Brain Barrier ◽

Normal Pressure Hydrocephalus ◽

Normal Pressure ◽

Brain Barrier ◽

Western Immunoblot ◽

Blood Brain

Abstract OBJECTIVE Traumatic brain injury (TBI) causes an increase in matrix metalloproteinases (MMPs), which are associated with neuroinflammation, blood-brain barrier disruption, hemorrhage, and cell death. We hypothesized that patients with TBI have an increase in MMPs in ventricular cerebrospinal fluid (CSF) and plasma. METHODS Patients with TBI and a ventricular catheter were entered into the study. Samples of CSF and plasma were collected at the time of catheter placement and at 24 and 72 hours after admission. Seven TBI patients were entered into the study, with 6 having complete data for analysis. Only patients who had a known time of insult that fell within a 6-hour window from initial insult to ventriculostomy were accepted into the study. Control CSF came from ventricular fluid in patients undergoing shunt placement for normal pressure hydrocephalus. Both MMP-2 and MMP-9 were measured with gelatin zymography and MMP-3 with Western immunoblot. RESULTS We found a significant elevation in the levels of the latent form of MMP-9 (92-kD) in the CSF obtained at the time of arrival (P < 0.05). Elevated levels of MMP-2 were detected in plasma at 72 hours, but not in the CSF. Using albumin from both CSF and blood, we calculated the MMP-9 index, which was significantly increased in the CSF, indicating endogenous MMP production. Western immunoblot showed elevated levels of MMP-3 in CSF at all times measured, whereas MMP-3 was not detected in the CSF of normal pressure hydrocephalus. CONCLUSION We show that MMPs are increased in the CSF of TBI patients. Although the number of patients was small, the results were robust and clearly demonstrated increases in MMP-3 and MMP-9 in ventricular CSF in TBI patients compared with controls. Although these preliminary results will need to be replicated, we propose that MMPs may be important in blood-brain barrier opening and hemorrhage secondary to brain injury in patients.

Download Full-text

Morphine attenuates neuroinflammation and blood-brain barrier disruption following traumatic brain injury through the opioidergic system

Brain Research Bulletin ◽

10.1016/j.brainresbull.2021.08.010 ◽

2021 ◽

Author(s):

Siavash Rahimi ◽

Behzad Dadfar ◽

Golvash Tavakolian ◽

Arya Asadi Rad ◽

Ali Rashid Sabkahi ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Opioidergic System ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption

Download Full-text

Oxygen radical mechanisms of brain injury following ischemia and reperfusion

Journal of Applied Physiology ◽

10.1152/jappl.1991.71.4.1185 ◽

1991 ◽

Vol 71 (4) ◽

pp. 1185-1195 ◽

Cited By ~ 469

Author(s):

R. J. Traystman ◽

J. R. Kirsch ◽

R. C. Koehler

Keyword(s):

Fatty Acids ◽

Brain Injury ◽

Free Fatty Acids ◽

Blood Brain Barrier ◽

Adenine Nucleotides ◽

Oxygen Radical ◽

Brain Barrier ◽

Ischemia And Reperfusion ◽

Radical Scavengers ◽

Blood Brain

This review addresses current understanding of oxygen radical mechanisms as they relate to the brain during ischemia and reperfusion. The mechanism for radical production remains speculative in large part because of the difficulty of measuring radical species in vivo. Breakdown of lipid membranes during ischemia leads to accumulation of free fatty acids. Decreased energy stores during ischemia result in the accumulation of adenine nucleotides. During reperfusion, metabolism of free fatty acids via the cyclooxygenase pathway and metabolism of adenine nucleotides via the xanthine oxidase pathway are the most likely sources of oxygen radicals. Although leukocytes have been found to accumulate in some models of ischemia and reperfusion, their mechanistic role remains in question. Therapeutic strategies aimed at decreasing brain injury have included administration of radical scavengers at the time of reperfusion. Efficacy of traditional oxygen radical scavengers such as superoxide dismutase and catalase may be limited by their inability to cross the blood-brain barrier. Lipid-soluble antioxidants appear more efficacious because of their ability to cross the blood-brain barrier and because of their presence in membrane structures where peroxidative reactions can be halted.

Download Full-text