Up-regulation of Wnt/β-catenin expression is accompanied with vascular repair after traumatic brain injury

Recent data suggest that repairing the cerebral vasculature after traumatic brain injury (TBI) may help to improve functional recovery. The Wnt/β-catenin signaling pathway promotes blood vessel formation during vascular development, but its role in vascular repair after TBI remains elusive. In this study, we examined how the cerebral vasculature responds to TBI and the role of Wnt/β-catenin signaling in vascular repair. We induced a moderate controlled cortical impact in adult mice and performed vessel painting to visualize the vascular alterations in the brain. Brain tissue around the injury site was assessed for β-catenin and vascular markers. A Wnt transgenic mouse line was utilized to evaluate Wnt gene expression. We report that TBI results in vascular loss followed by increases in vascular structure at seven days post injury (dpi). Immature, non-perfusing vessels were evident in the tissue around the injury site. β-catenin protein expression was significantly reduced in the injury site at 7 dpi. However, there was an increase in β-catenin expression in perilesional vessels at 1 and 7 dpi. Similarly, we found increased number of Wnt-GFP-positive vessels after TBI. Our findings suggest that Wnt/β-catenin expression contributes to the vascular repair process after TBI.

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Abstract W P260: Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

Stroke ◽

10.1161/str.46.suppl_1.wp260 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Alexander V Glushakov ◽

Jawad A Fazal ◽

Shuh Narumiya ◽

Sylvain Dore

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Young Adult ◽

Brain Injuries ◽

Neurological Deficits ◽

Cortical Lesions ◽

Brain Pathology ◽

Adult Mice ◽

Ep1 Receptor

Introduction: Brain injuries promote upregulation of so-called proinflammatory prostaglandin E2 leading to overactivation of a class of its cognate G-protein coupled receptors, notably EP1, which is considered as a promising target for treatment of ischemic stroke and, possibly, other neurological disorders involving excitotoxicity. However, our recent data suggest that of EP1 receptor in intracerebral hemorrhage may play a protective role. The goal of this study was to investigate a translational potential of EP1 receptor for treatment of traumatic brain injury (TBI). Methods: The acute brain injury was induced using controlled cortical impact (CCI) in wildtype (WT) and genetic EP1 receptor knockout mice (EP1-/-). Neurological deficit scores (NDS) and anatomical brain pathology were accessed at 48h after injury. Results: CCI resulted in significant cortical lesions, localized hippocampal edema and neurological deficits compared to animals from sham group underwent craniotomy only. The NDS after CCI were significantly higher in older mice (7-11mo) compared to young adult animals (2-4mo) in both WT and EP1-/- groups. Treatment with a selective antagonist SC-51089 with repeated doses of 20-100μg/kg after CCI had no significant effects on cortical lesions, hippocampal edema and NDS in young adult mice of both WT and EP1-/- genotypes. Post-treatment with 17-pt-PGE2 (300μg/kg) had no significant effects on anatomical brain pathology in young adult mice, but improved NDS at 24h in WT but not in EP1-/- mice. Immunohistochemistry revealed significant increases in GFAP and Iba1 immunoreactivity in selected brain regions surrounding injury suggesting astrogliosis and microglia activation. EP1 receptor knockout had no effects on GFAP and Iba1 expression in young adult mice, whereas lead to a significant attenuation of GFAP immunoreactivity in older mice. Conclusions: This study provides, for the first time, a clarification on the role of EP1 receptor in a preclinical model of contusive TBI. The results suggest that EP1 receptor might be involved in complex pathways differentially associated with neurological deficits. In addition, this study provides further clarification on clinical use of EP1 receptor ligands for treatment of acute brain injuries.

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Relevance of Blood Vessel Networks in Blast-Induced Traumatic Brain Injury

Computational and Mathematical Methods in Medicine ◽

10.1155/2015/928236 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Yi Hua ◽

Shengmao Lin ◽

Linxia Gu

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Blood Vessel ◽

Vessel Diameter ◽

Dynamic Responses ◽

Brain Dynamics ◽

Cerebral Vasculature ◽

Vessel Networks ◽

The Brain

Cerebral vasculature is a complex network that circulates blood through the brain. However, the role of this networking effect in brain dynamics has seldom been inspected. This work is to study the effects of blood vessel networks on dynamic responses of the brain under blast loading. Voronoi tessellations were implemented to represent the network of blood vessels in the brain. The brain dynamics in terms of maximum principal strain (MPS), shear strain (SS), and intracranial pressure (ICP) were monitored and compared. Results show that blood vessel networks significantly affected brain responses. The increased MPS and SS were observed within the brain embedded with vessel networks, which did not exist in the case without blood vessel networks. It is interesting to observe that the alternation of the ICP response was minimal. Moreover, the vessel diameter and density also affected brain dynamics in both MPS and SS measures. This work sheds light on the role of cerebral vasculature in blast-induced traumatic brain injury.

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Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury

ASN NEURO ◽

10.1177/1759091419847090 ◽

2019 ◽

Vol 11 ◽

pp. 175909141984709 ◽

Cited By ~ 2

Author(s):

Aleksandra Ichkova ◽

Andrew M. Fukuda ◽

Nina Nishiyama ◽

Germaine Paris ◽

Andre Obenaus ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Gap Junctions ◽

Motor Function ◽

Connexin 43 ◽

Post Injury ◽

Edema Formation ◽

Small Interference Rna ◽

Interference Rna

Juvenile traumatic brain injury (jTBI) is the leading cause of death and disability for children and adolescents worldwide, but there are no pharmacological treatments available. Aquaporin 4 (AQP4), an astrocytic perivascular protein, is increased after jTBI, and inhibition of its expression with small interference RNA mitigates edema formation and reduces the number of reactive astrocytes after jTBI. Due to the physical proximity of AQP4 and gap junctions, coregulation of AQP4 and connexin 43 (Cx43) expressions, and the possibility of water diffusion via gap junctions, we decided to address the potential role of astrocytic gap junctions in jTBI pathophysiology. We evaluated the role of Cx43 in the spread of the secondary injuries via the astrocyte network, such as edema formation associated with blood–brain barrier dysfunctions, astrogliosis, and behavioral outcome. We observed that Cx43 was altered after jTBI with increased expression in the perilesional cortex and in the hippocampus at several days post injury. In a second set of experiments, cortical injection of small interference RNA against Cx43 decreased Cx43 protein expression, improved motor function recovery, and decreased astrogliosis but did not result in differences in edema formation as measured via T2-weighted imaging or diffusion-weighted imaging at 1 day or 3 days. Based on our findings, we can speculate that while decreasing Cx43 has beneficial roles, it likely does not contribute to the spread of edema early after jTBI.

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1571: ROLE OF IL-17 AFTER TRAUMATIC BRAIN INJURY IN ADULT MICE

Critical Care Medicine ◽

10.1097/01.ccm.0000529572.79638.24 ◽

2018 ◽

Vol 46 (1) ◽

pp. 770-770

Author(s):

Dennis Simon ◽

Mandy McGeachy ◽

Itay Raphael ◽

Vincent Vagni ◽

Patrick Kochanek ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Adult Mice

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Traumatic Brain Injury-Associated Micrgoglia Adopt Longitudinal Transcriptional Changes Consistent with Long-Term Depression of Synaptic Strength

10.1101/422071 ◽

2018 ◽

Author(s):

Hadijat M. Makinde ◽

Talia B. Just ◽

Deborah R. Winter ◽

Steven J. Schwulst

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Synaptic Potentiation ◽

Post Injury ◽

Neurologic Impairment ◽

Mild Brain Injury ◽

Host Defense Response ◽

Transcriptional Changes

Traumatic brain injury (TBI) is an under-recognized public health threat. Even mild brain injury, or concussions, may lead to long-term neurologic impairment. Microglia play a fundamental role in the development and progression of this subsequent neurologic impairment. Despite this, a microglia-specific injury signature has yet to be identified. In the current study we hypothesized that TBI-associated microglia would adopt longitudinal changes in their transcriptional profile associated with pathways linked to the development of motor, cognitive, and behavioral disorders. C57BL/6 mice underwent TBI via a controlled cortical impact and were followed longitudinally. FACSorted microglia from TBI mice were subjected to RNA-sequencing at 7, 30, and 90 days post-injury. We identified 4 major patterns of gene expression corresponding to the host defense response, synaptic potentiation, lipid remodeling, and membrane polarization. In particular, significant upregulation of genes involved in long-term synaptic potentiation including Ptpn5, Shank3, and Sqstm1 were observed offering new insight into a previously unknown role of microglia in the weakening of synaptic efficacy between neurons after brain injury.

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Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent vs adult mice

10.1101/577999 ◽

2019 ◽

Author(s):

Fernanda Guilhaume-Correa ◽

Shelby M. Cansler ◽

Emily M. Shalosky ◽

Michael D. Goodman ◽

Nathan K. Evanson

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Recognition Performance ◽

Memory Performance ◽

Health Concern ◽

Post Injury ◽

Adult Mice ◽

Closed Head ◽

Old Adult ◽

Hippocampal Neurodegeneration

AbstractIntroductionTraumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year, of which about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent mice, using a closed head, single impact model of TBI.MethodsSix-week-old adolescent and 9-week-old adult male mice were subjected to TBI using a closed head weight drop model. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed.ResultsAdolescent TBI mice have increased mortality (X2= 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents, but not adults. Presence of hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased markers of astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days post-injury. Adolescents have memory deficits as evidenced by impaired novel object recognition performance 3 and 16 days post injury (F1,26 = 5.23, p = 0.031) while adults do not.ConclusionsAdults and adolescents within a close age range (6-9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts up to 16 days post injury.

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Response of the cerebral vasculature following traumatic brain injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17701460 ◽

2017 ◽

Vol 37 (7) ◽

pp. 2320-2339 ◽

Cited By ~ 85

Author(s):

Arjang Salehi ◽

John H Zhang ◽

Andre Obenaus

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Function ◽

Brain Injuries ◽

Critical Role ◽

Neurological Dysfunction ◽

Cerebral Hypoperfusion ◽

Cerebral Vasculature ◽

Vascular Repair ◽

Vascular Effects

The critical role of the vasculature and its repair in neurological disease states is beginning to emerge particularly for stroke, dementia, epilepsy, Parkinson’s disease, tumors and others. However, little attention has been focused on how the cerebral vasculature responds following traumatic brain injury (TBI). TBI often results in significant injury to the vasculature in the brain with subsequent cerebral hypoperfusion, ischemia, hypoxia, hemorrhage, blood–brain barrier disruption and edema. The sequalae that follow TBI result in neurological dysfunction across a host of physiological and psychological domains. Given the importance of restoring vascular function after injury, emerging research has focused on understanding the vascular response after TBI and the key cellular and molecular components of vascular repair. A more complete understanding of vascular repair mechanisms are needed and could lead to development of new vasculogenic therapies, not only for TBI but potentially vascular-related brain injuries. In this review, we delineate the vascular effects of TBI, its temporal response to injury and putative biomarkers for arterial and venous repair in TBI. We highlight several molecular pathways that may play a significant role in vascular repair after brain injury.

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Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology

Cells ◽

10.3390/cells10020199 ◽

2021 ◽

Vol 10 (2) ◽

pp. 199

Author(s):

Ryan D. Readnower ◽

William Brad Hubbard ◽

Olivia J. Kalimon ◽

James W. Geddes ◽

Patrick G. Sullivan

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Critical Role ◽

Neurological Deficits ◽

Cyclophilin D ◽

Cortical Tissue ◽

Post Injury ◽

Mptp Opening

Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/- mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI.

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