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Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury

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Traumatic brain injury (TBI) is acquired from an external force, which can inflict devastating effects to the brain vasculature and neighboring neuronal cells. Disruption of vasculature is a primary effect that can lead to a host of secondary injury cascades. The primary effects of TBI are rapidly occurring while secondary effects can be activated at later time points and may be more amenable to targeting. Primary effects of TBI include diffuse axonal shearing, changes in blood‐brain barrier (BBB) permeability, and brain contusions. These mechanical events, especially changes to the BBB, can induce calcium perturbations within brain cells producing secondary effects, which include cellular stress, inflammation, and apoptosis. These secondary effects can be potentially targeted to preserve the tissue surviving the initial impact of TBI. In the past, TBI research had focused on neurons without any regard for glial cells and the cerebrovasculature. Now a greater emphasis is being placed on the vasculature and the neurovascular unit following TBI. A paradigm shift in the importance of the vascular response to injury has opened new avenues of drug‐treatment strategies for TBI. However, a connection between the vascular response to TBI and the development of chronic disease has yet to be elucidated. Long‐term cognitive deficits are common amongst those sustaining severe or multiple mild TBIs. Understanding the mechanisms of cellular responses following TBI is important to prevent the development of neuropsychiatric symptoms. With appropriate intervention following TBI, the vascular network can perhaps be maintained and the cellular repair process possibly improved to aid in the recovery of cellular homeostasis. © 2015 American Physiological Society. Compr Physiol 5:1147‐1160, 2015.

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Figure 1. Figure 1. Pathophysiology of neuronal cell death following traumatic brain injury. An intracranial pressure spike, axonal shearing, and brain contusion contribute to secondary mechanisms that lead to an increase in Ca2+ channel opening. The generation of reactive oxygen species can ultimately contribute to cell death.
Figure 2. Figure 2. Depiction of a vasospasm resulting from traumatic brain injury. Vasospasm can be triggered by subarachnoid hemorrhage or blood pressure spikes. Pericytes near vessels release endothelin‐1, which triggers vasoconstriction.
Figure 3. Figure 3. The effects of traumatic brain injury on the blood‐brain barrier. TBI can cause disruptions of tight junction proteins connecting endothelial cells. Astrocytes can undergo astrogliosis and the basement membrane can become disrupted. Ultimately, these changes increase the likelihood of red blood cell extravasations.
Figure 4. Figure 4. Complex interplay of secondary mechanisms following traumatic brain injury. Secondary mechanisms of injury have multiple known effects. A few included are cellular necrosis, apoptosis, neurodegeneration, and tauopathy. Timing of activation and pathway connections are still being teased out with preclinical models of TBI.
Figure 5. Figure 5. The chronic effects of traumatic brain injury. Some individuals experiencing TBI are more susceptible to chronic effects than others. Environmental and genetic factors play a role. Pathologic changes that may develop include neurofibrillary tangles, axonal shearing, and amyloid plaques. Neuropsychiatric symptoms may also develop such as depression, impulsivity, cognitive decline, and confusion. These chronic effects following TBI remains a topic of growing importance receiving renewed research focus and funding.

Figure 1. Pathophysiology of neuronal cell death following traumatic brain injury. An intracranial pressure spike, axonal shearing, and brain contusion contribute to secondary mechanisms that lead to an increase in Ca2+ channel opening. The generation of reactive oxygen species can ultimately contribute to cell death.

Figure 2. Depiction of a vasospasm resulting from traumatic brain injury. Vasospasm can be triggered by subarachnoid hemorrhage or blood pressure spikes. Pericytes near vessels release endothelin‐1, which triggers vasoconstriction.

Figure 3. The effects of traumatic brain injury on the blood‐brain barrier. TBI can cause disruptions of tight junction proteins connecting endothelial cells. Astrocytes can undergo astrogliosis and the basement membrane can become disrupted. Ultimately, these changes increase the likelihood of red blood cell extravasations.

Figure 4. Complex interplay of secondary mechanisms following traumatic brain injury. Secondary mechanisms of injury have multiple known effects. A few included are cellular necrosis, apoptosis, neurodegeneration, and tauopathy. Timing of activation and pathway connections are still being teased out with preclinical models of TBI.

Figure 5. The chronic effects of traumatic brain injury. Some individuals experiencing TBI are more susceptible to chronic effects than others. Environmental and genetic factors play a role. Pathologic changes that may develop include neurofibrillary tangles, axonal shearing, and amyloid plaques. Neuropsychiatric symptoms may also develop such as depression, impulsivity, cognitive decline, and confusion. These chronic effects following TBI remains a topic of growing importance receiving renewed research focus and funding.
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Aric F. Logsdon, Brandon P. Lucke‐Wold, Ryan C. Turner, Jason D. Huber, Charles L. Rosen, James W. Simpkins. Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury. Compr Physiol 2015, 5: 1147-1160. doi: 10.1002/cphy.c140057