Mechanical Injury Induces Brain Endothelial-Derived Microvesicle Release: Implications for Cerebral Vascular Injury during Traumatic Brain Injury

This study examined the effect of posttraumatic hypoxia on cerebral vascular responsivity and axonal damage, while also exploring hypothermia's potential to attenuate these responses. Rats were subjected to impact acceleration injury (IAI) and equipped with cranial windows to assess vascular reactivity to topical acetylcholine, with postmortem analyses using antibodies to amyloid precursor protein to assess axonal damage. Animals were subjected to hypoxia alone, IAI and hypoxia, IAI and hypoxia before induction of moderate hypothermia (33°C), IAI and hypoxia induced during hypothermic intervention, and IAI and hypoxia initiated after hypothermia. Hypoxia alone had no impact on vascular reactivity or axonal damage. Acceleration injury and posttraumatic hypoxia resulted in dramatic axonal damage and altered vascular reactivity. When IAI and hypoxia were followed by hypothermic intervention, no axonal or vascular protection ensued. However, when IAI was followed by hypoxia induced during hypothermia, axonal and vascular protection followed. When this same hypoxic insult followed the use of hypothermia, no benefit ensued. These studies show that early hypoxia and delayed hypoxia exert damaging axonal and vascular consequences. Although this damage is attenuated by hypothermia, this follows only when hypoxia occurs during hypothermia, with no benefit found if the hypoxic insult proceeds or follows hypothermia.

Download Full-text

Assessment of Cerebral Vascular Dysfunction After Traumatic Brain Injury

Springer Protocols Handbooks - Animal Models of Acute Neurological Injuries II ◽

10.1007/978-1-61779-782-8_27 ◽

2012 ◽

pp. 263-273

Author(s):

Douglas S. DeWitt ◽

Donald S. Prough

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Dysfunction ◽

Cerebral Vascular

Download Full-text

Traumatic Cerebral Vascular Injury: The Effects of Concussive Brain Injury on the Cerebral Vasculature

Journal of Neurotrauma ◽

10.1089/089771503322385755 ◽

2003 ◽

Vol 20 (9) ◽

pp. 795-825 ◽

Cited By ~ 111

Author(s):

Douglas S. DeWitt ◽

Donald S. Prough

Keyword(s):

Brain Injury ◽

Vascular Injury ◽

Cerebral Vasculature ◽

Cerebral Vascular

Download Full-text

Low-level blast exposure induces chronic vascular remodeling, perivascular astrocytic degeneration and vascular-associated neuroinflammation

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01269-5 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Miguel A. Gama Sosa ◽

Rita De Gasperi ◽

Dylan Pryor ◽

Georgina S. Perez Garcia ◽

Gissel M. Perez ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Remodeling ◽

Late Onset ◽

Neurovascular Unit ◽

Microcomputed Tomography ◽

Collagen Type Iv ◽

Post Traumatic Stress ◽

Type Iv ◽

Cerebral Vascular

AbstractCerebral vascular injury as a consequence of blast-induced traumatic brain injury is primarily the result of blast wave-induced mechanical disruptions within the neurovascular unit. In rodent models of blast-induced traumatic brain injury, chronic vascular degenerative processes are associated with the development of an age-dependent post-traumatic stress disorder-like phenotype. To investigate the evolution of blast-induced chronic vascular degenerative changes, Long-Evans rats were blast-exposed (3 × 74.5 kPa) and their brains analyzed at different times post-exposure by X-ray microcomputed tomography, immunohistochemistry and electron microscopy. On microcomputed tomography scans, regional cerebral vascular attenuation or occlusion was observed as early as 48 h post-blast, and cerebral vascular disorganization was visible at 6 weeks and more accentuated at 13 months post-blast. Progression of the late-onset pathology was characterized by detachment of the endothelial and smooth muscle cellular elements from the neuropil due to degeneration and loss of arteriolar perivascular astrocytes. Development of this pathology was associated with vascular remodeling and neuroinflammation as increased levels of matrix metalloproteinases (MMP-2 and MMP-9), collagen type IV loss, and microglial activation were observed in the affected vasculature. Blast-induced chronic alterations within the neurovascular unit should affect cerebral blood circulation, glymphatic flow and intramural periarterial drainage, all of which may contribute to development of the blast-induced behavioral phenotype. Our results also identify astrocytic degeneration as a potential target for the development of therapies to treat blast-induced brain injury.

Download Full-text

CEREBRAL VASCULAR DYSFUNCTION FOLLOWING TRAUMATIC BRAIN INJURY

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.875.6 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Nuria Villalba‐Isabel ◽

Tram L Tran ◽

Mark T Nelson ◽

George C Wellman ◽

Kalev Freeman

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Dysfunction ◽

Cerebral Vascular

Download Full-text

Cerebral vascular responsiveness after experimental traumatic brain injury: the beneficial effects of delayed hypothermia combined with superoxide dismutase administration

Journal of Neurosurgery ◽

10.3171/jns/2008/109/9/0502 ◽

2008 ◽

Vol 109 (3) ◽

pp. 502-509 ◽

Cited By ~ 19

Author(s):

Anna I. Baranova ◽

Enoch P. Wei ◽

Yuji Ueda ◽

Milton M. Sholley ◽

Hermes A. Kontos ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Superoxide Dismutase ◽

Free Radical ◽

Brain Injury ◽

Vascular Function ◽

Free Radical Scavengers ◽

Therapeutic Window ◽

Radical Scavenger ◽

Vascular Protection ◽

Cerebral Vascular

Object Traumatic brain injury (TBI) induces cerebral vascular dysfunction reflected in altered responses to vasodilators such as acetylcholine and hypercapnia. It has been demonstrated that the use of either posttraumatic hypothermia or free radical scavengers offered vascular protection when those treatments were delivered early after the injury, losing efficacy when the initiation of either treatment was delayed. Because immediate posttraumatic treatment is not realistic in the clinical setting, the authors undertook this study to investigate whether the combination of delayed hypothermia and the delayed administration of the free radical scavenger superoxide dismutase (SOD) could result in improved vascular protection. Methods Male Sprague–Dawley rats were anesthetized and subjected to either an impact-acceleration or sham injury. Animals were treated either with hypothermia (32°C) initiated 60 minutes after TBI, delayed SOD (60 U/ml) applied 90 minutes after TBI, or a combination of delayed hypothermia (32°C) and delayed SOD (60 U/ml) applied 15 minutes prior to the cessation of hypothermia. In this investigation, the diameter of cerebral pial arterioles was measured at rest and then challenged with vasodilator acetylcholine and hypercapnia. Four vessels were assessed per animal prior to injury and then again up to 6 hours after injury. Results Delayed SOD treatment did not enhance vascular function, while delayed hypothermia treatment only partially preserved pial vascular function. However, the combination of delayed hypothermia and delayed SOD significantly preserved vascular function after the injury. Conclusions The results of these studies demonstrate that delayed hypothermia partially preserves vascular function after TBI, while expanding the therapeutic window over which agents such as SOD can now provide enhanced protection.

Download Full-text

Inhibition of the Electrogenic Na Pump Underlies Delayed Depolarization of Cortical Neurons After Mechanical Injury or Glutamate

Journal of Neurophysiology ◽

10.1152/jn.1997.77.2.632 ◽

1997 ◽

Vol 77 (2) ◽

pp. 632-638 ◽

Cited By ~ 51

Author(s):

Steven J. Tavalin ◽

Earl F. Ellis ◽

Leslie S. Satin

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Glutamate Receptor ◽

Cortical Neurons ◽

Superoxide Anion ◽

Receptor Activation ◽

Mechanical Injury ◽

Electrophysiological Response ◽

Na Pump ◽

Electrogenic Na Pump

Tavalin, Steven J., Earl. F. Ellis, and Leslie S. Satin. Inhibition of the electrogenic Na pump underlies delayed depolarization of cortical neurons after mechanical injury or glutamate. J. Neurophysiol. 77: 632–638, 1997. We previously characterized the electrophysiological response of cortical neurons to a brief sublethal stretch-injury using an in vitro model of traumatic brain injury. This model revealed that cortical neurons undergo a stretch-induced delayed depolarization (SIDD) of their resting membrane potential (RMP) which is ∼10 mV in magnitude. SIDD is dependent on N-methyl-d-aspartate (NMDA) receptor activation, neuronal firing, and extracellular calcium for its induction but not its maintenance. SIDD was maximal 1 h after the insult and required incubation at 37°C. The present study examined the mechanism mediating SIDD and its relation to glutamate receptor activation. The Na pump inhibitor ouabain was used to assess the contribution of the Na pump to the RMP of control and stretched neurons using whole cell patch-clamp techniques. The nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine and a polyethylene glycol conjugate of superoxide dismutase were used to assess whether NO or superoxide anion, respectively, were involved in the induction of SIDD. Neurons were exposed to exogenous glutamate in the absence of cell stretch to determine whether glutamate alone can mimic SIDD. We report that SIDD is mediated by Na pump inhibition and is likely to result from reduced energy levels since the RMP of neurons dialyzed with a pipette solution containing 5 mM ATP were identical to controls. NO, but not superoxide anion, also may contribute to SIDD. A 3-min exposure to 10 μM glutamate produced a SIDD-like depolarization also associated with Na pump inhibition. The results suggest that Na pump inhibition secondary to alterations in cellular energetics underlies SIDD. Na pump inhibition due to glutamate exposure may contribute to traumatic brain injury or neurodegenerative diseases linked to glutamate receptor activation.

Download Full-text