Activation of the Hedgehog Pathway Promotes Recovery of Neurological Function After Traumatic Brain Injury by Protecting the Neurovascular Unit

2020 ◽  
Vol 11 (4) ◽  
pp. 720-733 ◽  
Author(s):  
Jingchuan Wu ◽  
Junchi He ◽  
Xiaocui Tian ◽  
Jianjun Zhong ◽  
Hui Li ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurovascular Unit ◽  
Neurological Function ◽  
Hedgehog Pathway

scholarly journals Bone Marrow Stromal Cells Promote Neuronal Restoration in Rats with Traumatic Brain Injury: Involvement of GDNF Regulating BAD and BAX Signaling

2016 ◽  
Vol 38 (2) ◽  
pp. 748-762 ◽  
Author(s):  
Qin Shen ◽  
Yong Yin ◽  
Qing-Jie Xia ◽  
Na Lin ◽  
You-Cui Wang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Bone Marrow ◽  
Brain Injury ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Fluorescent Protein ◽  
Neurological Function ◽  
Marrow Stromal Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Green Fluorescent

Background/Aims: To investigate the effects of bone marrow stromal cells (BMSCs) and underlying mechanisms in traumatic brain injury (TBI). Methods: Cultured BMSCs from green fluorescent protein-transgenic mice were isolated and confirmed. Cultured BMSCs were immediately transplanted into the regions surrounding the injured-brain site to test their function in rat models of TBI. Neurological function was evaluated by a modified neurological severity score on the day before, and on days 7 and 14 after transplantation. After 2 weeks of BMSC transplantation, the brain tissue was harvested and analyzed by microarray assay. And the coronal brain sections were determined by immunohistochemistry with mouse anti-growth-associated protein-43 kDa (anti-GAP-43) and anti-synaptophysin to test the effects of transplanted cells on the axonal regeneration in the host brain. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and Western blot were used to detect the apoptosis and expression of BAX and BAD. Results: Microarray analysis showed that BMSCs expressed growth factors such as glial cell-line derived neurotrophic factor (GDNF). The cells migrated around the injury sites in rats with TBI. BMSC grafts resulted in an increased number of GAP-43-immunopositive fibers and synaptophysin-positive varicosity, with suppressed apoptosis. Furthermore, BMSC transplantation significantly downregulated the expression of BAX and BAD signaling. Moreover, cultured BMSC transplantation significantly improved rat neurological function and survival. Conclusion: Transplanted BMSCs could survive and improve neuronal behavior in rats with TBI. Mechanisms of neuroprotection and regeneration were involved, which could be associated with the GDNF regulating the apoptosis signals through BAX and BAD.

scholarly journals Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

2019 ◽  
Vol 20 (24) ◽  
pp. 6125 ◽  
Author(s):  
Ning Liu ◽  
Yinghua Jiang ◽  
Joon Yong Chung ◽  
Yadan Li ◽  
Zhanyang Yu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Neurovascular Unit ◽  
Annexin A2 ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Endogenous Factors ◽  
The Brain

Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

Repair of Neurological Function in Response to FK506 Through CaN/NFATc1 Pathway Following Traumatic Brain Injury in Rats

2016 ◽  
Vol 41 (10) ◽  
pp. 2810-2818 ◽  
Author(s):  
Qiaoli Wu ◽  
Guodong Liu ◽  
Lixia Xu ◽  
Xiaochang Wen ◽  
Ying Cai ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurological Function

scholarly journals Hyperbaric oxygen for severe traumatic brain injury: a randomized trial

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052093982
Author(s):  
Xianliang Zhong ◽  
Aijun Shan ◽  
Jianzhong Xu ◽  
Jian Liang ◽  
Ying Long ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Hyperbaric Oxygen ◽  
Severe Traumatic Brain Injury ◽  
Hyperbaric Oxygen Therapy ◽  
Oxygen Therapy ◽  
Vital Signs ◽  
Neurological Function ◽  
Control Group ◽  
Experimental Group

Objective The present study aimed to explore the effects of hyperbaric oxygen therapy on the prognosis and neurological function of patients with severe traumatic brain injury. Methods A prospective study was carried out in 88 patients diagnosed with severe brain injury at our hospital and they were enrolled as research participants and randomly assigned to control and experimental groups (n = 44 per group) using a random number table method. Both groups underwent routine treatment. Patients in the experimental group were administered hyperbaric oxygen therapy approximately 1 week after admission when their vital signs had stabilized. Results No significant intergroup differences were observed in the Glasgow Coma Scale (GCS) and U.S. National Institutes of Health Stroke Scale (NIHSS) scores before treatment. However, after oxygen treatment, compared with the control group, the experimental group showed higher GCS and lower NIHSS scores. The GCS score at admission, tracheotomy status, and first hyperbaric oxygen therapy duration were independent prognostic factors in patients with severe traumatic brain injury. Conclusion Hyperbaric oxygen therapy may promote recovery of neurological function and improve the cognitive function and prognosis of patients with severe traumatic brain injury.

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

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.

scholarly journals Digital signatures for early traumatic brain injury outcome prediction in the intensive care unit

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anil K. Palepu ◽  
Aditya Murali ◽  
Jenna L. Ballard ◽  
Robert Li ◽  
Samiksha Ramesh ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Traumatic Brain Injury ◽  
Intensive Care ◽  
Brain Injury ◽  
Neurological Function ◽  
Series Data ◽  
Admission Diagnosis ◽  
Electronic Health Record Data ◽  
Prediction Of Mortality ◽  
Icu Discharge

AbstractTraumatic brain injury (TBI) is a leading neurological cause of death and disability across the world. Early characterization of TBI severity could provide a window for therapeutic intervention and contribute to improved outcome. We hypothesized that granular electronic health record data available in the first 24 h following admission to the intensive care unit (ICU) can be used to differentiate outcomes at discharge. Working from two ICU datasets we focused on patients with a primary admission diagnosis of TBI whose length of stay in ICU was ≥ 24 h (N = 1689 and 127). Features derived from clinical, laboratory, medication, and physiological time series data in the first 24 h after ICU admission were used to train elastic-net regularized Generalized Linear Models for the prediction of mortality and neurological function at ICU discharge. Model discrimination, determined by area under the receiver operating characteristic curve (AUC) analysis, was 0.903 and 0.874 for mortality and neurological function, respectively. Model performance was successfully validated in an external dataset (AUC 0.958 and 0.878 for mortality and neurological function, respectively). These results demonstrate that computational analysis of data routinely collected in the first 24 h after admission accurately and reliably predict discharge outcomes in ICU stratum TBI patients.

scholarly journals Temporal Profile of Transporter mRNA Expression in the Brain after Traumatic Brain Injury in Developing Rats

2019 ◽  
Author(s):  
Solomon M. Adams ◽  
Fanuel T. Hagos ◽  
Jeffrey P. Cheng ◽  
Robert S. B. Clark ◽  
Patrick M. Kochanek ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mrna Expression ◽  
Neurovascular Unit ◽  
Post Injury ◽  
Adult Rats ◽  
Order Of Magnitude ◽  
Liver And Kidney ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTTraumatic brain injury (TBI) is a leading cause of death in children and young adults; however, new pharmacologic approaches have failed to improve outcomes in clinical trials. Transporter proteins are central to the maintenance of homeostasis within the neurovascular unit, and regulate drug penetration into the brain. Our objective was to measure transporter temporal changes in expression in the hippocampus and cortex after experimental TBI in developing rats. We also evaluated the expression of transporters in brain, liver, and kidney across the age spectrum in both pediatric and adult rats. Eighty post-natal day (PND)-17 rats and four adult rats were randomized to receive controlled cortical impact (CCI), sham surgery, or no surgery. mRNA transcript counts for 27 ATP-binding cassette and solute carrier transporters were measured in the hippocampus, cortex, choroid plexus, liver, and kidney at 3h, 12h, 24h, 72h, 7d, and 14d post injury. After TBI, the expression of many transporters (Abcc2, Slc15a2, Slco1a2) decreased significantly in the first 24 hours, with a return to baseline over 7-14 days. Some transporters (Abcc4, Abab1a/b, Slc22a4) showed a delayed increase in expression. Baseline expression of transporters was of a similar order of magnitude in brain tissues relative to liver and kidney. Findings suggest that transporter-regulated processes may be impaired in the brain early after TBI and are potentially involved in the recovery of the neurovascular unit. Our data also suggest that transport-dependent processes in the brain are of similar importance as those seen in organs involved in drug metabolism and excretion.Significance StatementBaseline transporter mRNA expression in the central nervous system is of similar magnitude as liver and kidney, and experimental traumatic brain injury is associated with acute decrease in expression of several transporters, while others show delayed increase or decrease in expression. Pharmacotherapy following traumatic brain injury should consider potential pharmacokinetic changes associated with transporter expression.

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