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

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141984709 ◽  
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.

scholarly journals A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

2017 ◽  
Vol 38 (10) ◽  
pp. 1818-1827 ◽  
Author(s):  
Raghavendar Chandran ◽  
TaeHee Kim ◽  
Suresh L Mehta ◽  
Eshwar Udho ◽  
Vishal Chanana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Function ◽  
Neurological Dysfunction ◽  
Vehicle Group ◽  
Lesion Volume ◽  
Post Injury ◽  
Cortical Contusion ◽  
Nrf2 Activator

Uncontrolled oxidative stress contributes to the secondary neuronal death that promotes long-term neurological dysfunction following traumatic brain injury (TBI). Surprisingly, both NADPH oxidase 2 (NOX2) that increases and transcription factor Nrf2 that decreases reactive oxygen species (ROS) are induced after TBI. As the post-injury functional outcome depends on the balance of these opposing molecular pathways, we evaluated the effect of TBI on the motor and cognitive deficits and cortical contusion volume in NOX2 and Nrf2 knockout mice. Genetic deletion of NOX2 improved, while Nrf2 worsened the post-TBI motor function recovery and lesion volume indicating that decreasing ROS levels might be beneficial after TBI. Treatment with either apocynin (NOX2 inhibitor) or TBHQ (Nrf2 activator) alone significantly improved the motor function after TBI, but had no effect on the lesion volume, compared to vehicle control. Whereas, the combo therapy (apocynin + TBHQ) given at either 5 min/24 h or 2 h/24 h improved motor and cognitive function and decreased cortical contusion volume compared to vehicle group. Thus, both the generation and disposal of ROS are important modulators of oxidative stress, and a combo therapy that prevents ROS formation and potentiates ROS disposal concurrently is efficacious after TBI.

scholarly journals The Role of Bradykinin B1 and B2 Receptors for Secondary Brain Damage after Traumatic Brain Injury in Mice

2009 ◽  
Vol 30 (1) ◽  
pp. 130-139 ◽  
Author(s):  
Raimund Trabold ◽  
Christian Erös ◽  
Klaus Zweckberger ◽  
Jane Relton ◽  
Heike Beck ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Functional Outcome ◽  
Brain Edema ◽  
Brain Damage ◽  
Secondary Brain Damage ◽  
Edema Formation ◽  
Receptor Mrna ◽  
B2 Receptors

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B1-, and B2-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma ( P<0.01 versus sham). Kinin B1 receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B1 and B2 receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B2R−/− mice had significantly less brain edema (−51% versus WT, 24 h; P<0.001), smaller contusion volumes (∼50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice ( P<0.05). The present results show that bradykinin and its B2 receptors play a causal role for brain edema formation and cell death after TBI.

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

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.

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

2017 ◽  
Vol 38 (2) ◽  
pp. 274-289 ◽  
Author(s):  
Arjang Salehi ◽  
Amandine Jullienne ◽  
Mohsen Baghchechi ◽  
Mary Hamer ◽  
Mark Walsworth ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Repair Process ◽  
Cerebral Vasculature ◽  
Vascular Repair ◽  
Post Injury ◽  
Injury Site ◽  
Transgenic Mouse Line ◽  
Adult Mice

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.

scholarly journals Hypoxia-Inducible Factor 1 is Essential for Spontaneous Recovery from Traumatic Brain Injury and is a Key Mediator of Heat Acclimation Induced Neuroprotection

2013 ◽  
Vol 33 (4) ◽  
pp. 524-531 ◽  
Author(s):  
Gali Umschweif ◽  
Alexander G Alexandrovich ◽  
Victoria Trembovler ◽  
Michal Horowitz ◽  
Esther Shohami
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Function ◽  
Spontaneous Recovery ◽  
Hypoxia Inducible Factor ◽  
Heat Acclimation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lesion Volume ◽  
Edema Formation ◽  
Glucose Transporter 1

Heat acclimation (HA), a well-established preconditioning model, confers neuroprotection in rodent models of traumatic brain injury (TBI). It increases neuroprotective factors, among them is hypoxia-inducible factor 1α (HIF-1α), which is important in the response to postinjury ischemia. However, little is known about the role of HIF-1α in TBI and its contribution to the establishment of the HA protecting phenotype. Therefore, we aimed to explore HIF-1α role in TBI defense mechanisms as well as in HA-induced neuroprotection. Acriflavine was used to inhibit HIF-1 in injured normothermic (NT) or HA mice. After TBI, we evaluated motor function recovery, lesion volume, edema formation, and body temperature as well as HIF-1 downstream transcription targets, such as glucose transporter 1 (GLUT1), vascular endothelial growth factor, and aquaporin 4. We found that HIF-1 inhibition resulted in deterioration of motor function, increased lesion volume, hypothermia, and reduced edema formation. All these parameters were significantly different in the HA mice. Western blot analysis and enzyme-linked immunosorbent assay showed reduced levels of all HIF-1 downstream targets in HA mice, however, only GLUT1 was downregulated in NT mice. We conclude that HIF-1 is a key mediator in both spontaneous recovery and HA-induced neuroprotection after TBI.

scholarly journals DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood–Brain Barrier Permeability

2020 ◽  
Vol 21 (17) ◽  
pp. 6291
Author(s):  
Zhuo-Hao Liu ◽  
Nan-Yu Chen ◽  
Po-hsun Tu ◽  
Chen-Te Wu ◽  
Shao-Chieh Chiu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Blood Brain Barrier ◽  
Temporal Analysis ◽  
Brain Barrier ◽  
Functional Improvement ◽  
Post Injury ◽  
Edema Formation ◽  
Mortality And Morbidity ◽  
Blood Brain

Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood–brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI.

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

Cells ◽  
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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