scholarly journals Neuroprotective Roles of the Adenosine A3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury

2021 ◽  
Author(s):  
Eda Bozdemir ◽  
Fabio A Vigil ◽  
Sang H Chun ◽  
Liliana Espinoza ◽  
Vladislav Bugay ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Contextual Fear Conditioning ◽  
Long Term Memory ◽  
Secondary Brain Injury ◽  
Post Injury ◽  
Adenosine A3 Receptor ◽  
Atp Production ◽  
Neuroprotective Efficacy

Abstract Background: Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported stimulation of astrocyte mitochondrial metabolism by P2Y1 receptor agonists significantly reduced cerebral edema and reactive gliosis in a TBI model. Subsequent data on the pharmacokinetics (PK) and rapid metabolism of these compounds suggested neuroprotection was likely mediated by a metabolite, AST-004, which binding data indicated was an adenosine A3 receptor (A3R) agonist. Methods: The neuroprotective efficacy of AST-004 was tested in a controlled closed cortical injury (CCCI) model of TBI in mice. Results: Twenty-four (24) hours post-injury, mice subjected to CCCI and treated with AST-004 (0.22mg/kg) exhibited significantly less secondary brain injury. These effects were quantified with less cell death (PSVue794 fluorescence) and loss of blood brain barrier breakdown (Evans Blue extravasation assay), compared to vehicle treated TBI mice. TBI treated mice also exhibited significantly reduced neuroinflammatory markers, glial-fibrillary acidic protein (GFAP, astrogliosis) and ionized Ca2+ binding adaptor molecule 1 (Iba1, microgliosis), both at the mRNA (gRT-PCR) and protein (western blot and immunofluorescence) levels, respectively. Four (4) weeks post-injury, AST-004 treated TBI mice presented significantly reduced impairment of long-term memory. Spatial memory was assessed with a contextual fear conditioning behavior assay (freezing behavior after shock). Finally, AST-004 treatments were found to increase in vivo ATP production in astrocytes (gfap-targeted luciferase activity), consistent with the proposed mechanism of action. Conclusions: These data reveal AST-004 as a novel A3R agonist that increases astrocyte energy production and enhances their neuroprotective efficacy after brain injury.

scholarly journals Traumatic Brain Injury as a Disorder of Brain Connectivity

2016 ◽  
Vol 22 (2) ◽  
pp. 120-137 ◽  
Author(s):  
Jasmeet P. Hayes ◽  
Erin D. Bigler ◽  
Mieke Verfaellie
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Functional Connectivity ◽  
Negative Impact ◽  
Axonal Injury ◽  
Resting State Functional Connectivity ◽  
Post Injury ◽  
Recent Advances

AbstractObjectives:Recent advances in neuroimaging methodologies sensitive to axonal injury have made it possible to assess in vivo the extent of traumatic brain injury (TBI) -related disruption in neural structures and their connections. The objective of this paper is to review studies examining connectivity in TBI with an emphasis on structural and functional MRI methods that have proven to be valuable in uncovering neural abnormalities associated with this condition.Methods:We review studies that have examined white matter integrity in TBI of varying etiology and levels of severity, and consider how findings at different times post-injury may inform underlying mechanisms of post-injury progression and recovery. Moreover, in light of recent advances in neuroimaging methods to study the functional connectivity among brain regions that form integrated networks, we review TBI studies that use resting-state functional connectivity MRI methodology to examine neural networks disrupted by putative axonal injury.Results:The findings suggest that TBI is associated with altered structural and functional connectivity, characterized by decreased integrity of white matter pathways and imbalance and inefficiency of functional networks. These structural and functional alterations are often associated with neurocognitive dysfunction and poor functional outcomes.Conclusions:TBI has a negative impact on distributed brain networks that lead to behavioral disturbance. (JINS, 2016,22, 120–137)

scholarly journals Rapid disruption of the cortical microcirculation after mild traumatic brain injury

2019 ◽  
Author(s):  
Ellen D. Witkowski ◽  
Şefik Evren Erdener ◽  
Kıvılcım Kılıç ◽  
Sreekanth Kura ◽  
Jianbo Tang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Vascular Dysfunction ◽  
Metabolic Stress ◽  
Time Lapse ◽  
Post Injury ◽  
Injury Model ◽  
Time Lapse Imaging

AbstractTraumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can still lead to long-term neuropathology manifesting months or years later. Although the cellular stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to characterize deficits in the cortical microcirculation during both acute and chronic phases after mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking flow deficits in the capillary network, where 18% of vessels were completely occluded for extended periods after injury, and an additional >50% showed substantial stoppages. Decreased CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that acute post-injury periods may be key therapeutic windows for interventions that restore flow and mitigate metabolic stress.

scholarly journals Refined Analysis of Chronic White Matter Changes after Traumatic Brain Injury and Repeated Sports-Related Concussions: Of Use in Targeted Rehabilitative Approaches?

2022 ◽  
Vol 11 (2) ◽  
pp. 358
Author(s):  
Francesco Latini ◽  
Markus Fahlström ◽  
Fredrik Vedung ◽  
Staffan Stensson ◽  
Elna-Marie Larsson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Diffusion Tensor ◽  
Global Analysis ◽  
Memory Performance ◽  
Regional Analysis ◽  
Long Term Memory ◽  
Post Injury ◽  
White Matter Changes

Traumatic brain injury (TBI) or repeated sport-related concussions (rSRC) may lead to long-term memory impairment. Diffusion tensor imaging (DTI) is helpful to reveal global white matter damage but may underestimate focal abnormalities. We investigated the distribution of post-injury regional white matter changes after TBI and rSRC. Six patients with moderate/severe TBI, and 12 athletes with rSRC were included ≥6 months post-injury, and 10 (age-matched) healthy controls (HC) were analyzed. The Repeatable Battery for the Assessment of Neuropsychological Status was performed at the time of DTI. Major white matter pathways were tracked using q-space diffeomorphic reconstruction and analyzed for global and regional changes with a controlled false discovery rate. TBI patients displayed multiple classic white matter injuries compared with HC (p < 0.01). At the regional white matter analysis, the left frontal aslant tract, anterior thalamic radiation, and the genu of the corpus callosum displayed focal changes in both groups compared with HC but with different trends. Both TBI and rSRC displayed worse memory performance compared with HC (p < 0.05). While global analysis of DTI-based parameters did not reveal common abnormalities in TBI and rSRC, abnormalities to the fronto-thalamic network were observed in both groups using regional analysis of the white matter pathways. These results may be valuable to tailor individualized rehabilitative approaches for post-injury cognitive impairment in both TBI and rSRC patients.

scholarly journals N-arachidonoyl-L-serine (AraS) Possesses Proneurogenic Properties in Vitro and in Vivo after Traumatic Brain Injury

2013 ◽  
Vol 33 (8) ◽  
pp. 1242-1250 ◽  
Author(s):  
Ayelet Cohen-Yeshurun ◽  
Dafna Willner ◽  
Victoria Trembovler ◽  
Alexander Alexandrovich ◽  
Raphael Mechoulam ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cannabinoid Receptor ◽  
Fold Increase ◽  
Lesion Volume ◽  
Post Injury ◽  
Neuroprotective Effects ◽  
Neurobehavioral Function

N-arachidonoyl-L-serine (AraS) is a novel neuroprotective endocannabinoid. We aimed to test the effects of exogenous AraS on neurogenesis after traumatic brain injury (TBI). The effects of AraS on neural progenitor cells (NPC) proliferation, survival, and differentiation were examined in vitro. Next, mice underwent TBI and were treated with AraS or vehicle. Lesion volumes and clinical outcome were evaluated and the effects on neurogenesis were tested using immunohistochemistry. Treatment with AraS led to a dose-dependent increase in neurosphere size without affecting cell survival. These effects were partially reversed by CB1, CB2, or TRPV1 antagonists. AraS significantly reduced the differentiation of NPC in vitro to astrocytes or neurons and led to a 2.5-fold increase in expression of the NPC marker nestin. Similar effects were observed in vivo in mice treated with AraS 7 days after TBI. These effects were accompanied by a reduction in lesion volume and an improvement in neurobehavioral function compared with controls. AraS increases proliferation of NPCs in vitro in cannabinoid-receptor-mediated mechanisms and maintains NPC in an undifferentiated state in vitro and in vivo. Moreover, although given at 7 days post injury, these effects are associated with significant neuroprotective effects leading to an improvement in neurobehavioral functions.

scholarly journals Analysis of Neuron Specific Enolase Serum Levels in Traumatic Brain Injury

2021 ◽  
Vol 5 (4) ◽  
pp. 1218-1222
Author(s):  
Yuliarni Syafrita ◽  
Nora Fitri
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Injuries ◽  
Neuron Specific Enolase ◽  
Serum Levels ◽  
Pathological Process ◽  
P Value ◽  
Secondary Brain Injury ◽  
Post Injury ◽  
The Brain

Background : Traumatic brain injury is still the main cause of death and disability in productive age. Assessment the level of consciousness and imaging examinations after a brain injury can not always describe the severity of damage in the brain, this is because the pathological process is still ongoing due to secondary brain injury. Therefore, it is necessary to examine biomarkers that can describe the severity of the pathological process that occurs. The purpose of this study was to assess serum neuron-specific enolase (NSE) levels and their relationship to the severity and outcome of a traumatic brain injury. Methods : A cross sectional design was conducted in the emergency department of DR M Djamil Hospital, Padang. There were 72 patients who met the inclusion criteria. A Glasgow Coma Scale examination was performed to assess the severity of brain injury and examination of NSE serum levels at 48 hours post- injury using ELISA technique and assess the Glasgow outcome scale (GOS) at 6 weeks post-injury. Data analysis using SPSS 22 program, the results are significance if the p value <0.05  Results : The average NSE level was higher in severe brain injuries than moderate and mild brain injuries and this difference was statistically significant (p<0.05).  The NSE serum levels were higher in poor outcomes than in good outcomes and this difference was statistically significant (p<0.05).  Conclusion : High NSE serum levels in the acute phase were associated with the severity of the brain injury and poor outcome 6 weeks after the brain injury. 

scholarly journals Uncovering temporally sensitive targeting motifs for traumatic brain injury via phage display

2020 ◽  
Author(s):  
Briana I. Martinez ◽  
Gergey Alzaem Mousa ◽  
Kiera Fleck ◽  
Tara MacCulloch ◽  
Chris W. Diehnelt ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Phage Display ◽  
Biomarker Discovery ◽  
Phage Display Library ◽  
Diagnostic Tools ◽  
Post Injury ◽  
Candidate Target ◽  
Discovery Pipeline

AbstractThe heterogeneous injury pathophysiology of traumatic brain injury (TBI) is a barrier to developing highly sensitive and specific diagnostic tools. Embracing neural injury complexity is critical for the development and advancement of diagnostics and therapeutics. The current study employs a unique discovery pipeline to identify targeting motifs that recognize specific phases of TBI pathology. This pipeline entails in vivo biopanning with a domain antibody (dAb) phage display library, next generation sequencing (NGS) analysis, and peptide synthesis. Here, we identify targeting motifs based on the HCDR3 structure of dAbs for acute (1 day) and subacute (7 days) post-injury timepoints using a mouse controlled cortical impact model. Their bioreactivity was validated using immunohistochemistry and candidate target epitopes were identified via immunoprecipitation-mass spectrometry. The acute targeting motif recognizes targets associated with metabolic and mitochondrial dysfunction whereas the subacute motif was largely associated with neurodegenerative processes. This phage display biomarker discovery pipeline for TBI successfully achieved discovery of temporally specific TBI targeting motif/epitope pairs that will advance the TBI diagnostics and therapeutics.

scholarly journals N-docosahexaenoylethanolamine reduces neuroinflammation and cognitive impairment after mild traumatic brain injury in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arina I. Ponomarenko ◽  
Anna A. Tyrtyshnaia ◽  
Evgeny A. Pislyagin ◽  
Inessa V. Dyuizen ◽  
Ruslan M. Sultanov ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Therapeutic Potential ◽  
Neurotropic Activity ◽  
Microglial Cells ◽  
Long Term Memory ◽  
Sod Production

AbstractAt present, there is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acids ethanolamides (N-acylethanolamines). N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analogue of anandamide, a widely studied endocannabinoid derived from arachidonic acid. The results of this study demonstrate that DHEA, when administered subcutaneously (10 mg/kg/day, 7 days), promotes cognitive recovery in rats subjected to mild traumatic brain injury (mTBI). In the cerebral cortex of experimental animals, we analyzed the dynamics of Iba-1-positive microglia activity changes and the expression of pro-inflammatory markers (IL1β, IL6, CD86). We used immortalized mouse microglial cells (SIM-A9) to assess the effects of DHEA on LPS-induced cytokines/ROS/NO/nitrite, as well as on CD206 (anti-inflammatory microglia) and the antioxidant enzyme superoxide dismutase (SOD) production. In vivo and in vitro experiments showed that DHEA: (1) improves indicators of anxiety and long-term memory; (2) inhibits the pro-inflammatory microglial cells activity; (3) decrease the level of pro-inflammatory cytokines/ROS/NO/nitrites; (4) increase CD206 and SOD production. In general, the results of this study indicate that DHEA has a complex effect on the neuroinflammation processes, which indicates its high therapeutic potential.

scholarly journals 513 Understanding the Role of HMGB1 Post-Traumatic Brain Injury - The Complex Interplay Between Neuro-Inflammation and Neurogenesis

2021 ◽  
Vol 108 (Supplement_2) ◽  
Author(s):  
O Marei ◽  
S Manivannan ◽  
O Elalfy ◽  
M Zaben
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Current Evidence ◽  
Post Injury ◽  
Term Survival ◽  
Positive Effects ◽  
Pubmed Database ◽  
Post Traumatic

Abstract Introduction Traumatic brain injury (TBI) is a global public health burden. Although neurogenesis occurs post-injury, achieving long term survival of newly generated neurons remains elusive. High Mobility Group Box protein 1 (HMGB1) is a pivotal cytokine in hosting the neuro-inflammatory response to injury, but also mediates neurogenesis during physiological development. In this review, we examine current evidence for post-traumatic neurogenesis and HMGB1 as a therapeutic target. Method PubMed database was evaluated with the following search terms: HMGB1, isoforms, neurogenesis, traumatic brain injury, Toll-like receptor, receptor for advanced glycation end-products. Results Multiple studies support the existence of neurogenesis post-injury both in vitro and in vivo. Different HMGB1 target receptors mediate different functions of HMGB1, though these are not mutually exclusive in the context of injury. Interaction with RAGE is responsible for developmental neurogenesis, whilst TLR-4 mediates the innate immune response. Though different HMGB1 isoforms are recognised, specific effects post-injury remains unexplored. In vivo animal studies demonstrate positive effects of HMGB1 antagonism post-TBI, but long-term outcomes remain unclear. Conclusions Modulating HMGB1 may enhance post-TBI recovery, but a mechanistic understanding of its effects on neurogenesis is fundamental to avoid negating potentially beneficial effects.

scholarly journals Cerebrovascular and neurological impact of chronic smoking on post traumatic brain injury outcome and recovery: an in vivo study

2019 ◽  
Author(s):  
Farzane Sivandzade ◽  
Faleh Alqahtani ◽  
Ali Sifat ◽  
Luca Cucullo
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Vascular Inflammation ◽  
Post Injury ◽  
Transcript Factor ◽  
Weight Drop ◽  
Post Traumatic ◽  
Chronic Smoking ◽  
Age Range

Abstract Background: Traumatic Brain Injury (TBI) is among the most prevalent causes of cerebrovascular and neurological damage worldwide. To this end, tobacco smoking (TS) has been shown to promote vascular inflammation, neurovascular impairments and risk of cerebrovascular and neurological disorders through oxidative stress (OS) stimuli targeting the blood-brain barrier (BBB) endothelium among others. It has been recently suggested that premorbid conditions such as TS may exacerbate post-TBI brain damage and impact recovery. The present study aims to investigate and dissect out the pathophysiological mechanisms underlying the exacerbation of TBI in a weight-drop model following chronic TS exposure. Methods: C57BL/6J male mice, age range 6–8 weeks were chronically exposed to TS for three weeks. Test animals were then subjected to TBI by guided vertical head weight drop using a 30 g metal weight free felling from an 80 cm distance before reaching the target. Physical activity and body weight of the mice were analyzed before TBI and 1 h, 24 h and 3 days post-injury. Finally, mice were sacrificed to collect blood and brain samples for subsequent biochemical and molecular analysis. Western blotting was applied to assess the expression of Nrf2 (a key antioxidant transcription factor) as well as tight junction proteins associated with BBB integrity including, ZO-1, Occludin, Claudin-5 from brain tissues homogenates. Levels of NF-kB (a pro-inflammatory transcript factor which antagonizes Nrf2 activity) along with pro-inflammatory cytokines IL-6, IL-10 and TNF-α were measured by ELISA on blood samples. Results: TS promoted significantly increased inflammation and loss of BBB integrity in TBI when compared to TS-Free test mice. Additionally, mice chronically exposed to TS prior to TBI experienced a more significant weight loss, behavioral, and motor activity deficiency and slower post-TBI recovery when compared to TS-free TBI mice. Conclusion: TS promotes a significant exacerbation of post-TBI neurovascular and neurological impairments. Whereas BBB impairment and pro-inflammatory vascular responses induced by chronic TS exposure are likely responsible for the retardation of post-traumatic recovery observed in these animals.

scholarly journals Widespread Cortical Demyelination in Geriatric Cases of Mild Traumatic Brain Injury and in Alzheimer’s Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 677-677
Author(s):  
Andrei Irimia ◽  
Nahian Chowdhury ◽  
Shania Wang ◽  
Sean Mahoney ◽  
Van Ngo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Bias Field ◽  
Future Research ◽  
Post Injury ◽  
Temporal Lobes

Abstract Cortical demyelination is related to neurodegeneration after mild traumatic brain injury (mTBI) and Alzheimer’s disease (AD). The ratio R of T1-to-T2-weighted magnetic resonance image (MRI) intensities is proportional to myelin content, and allows myelin changes to be mapped in vivo. T1 and T2 MRIs were acquired from mTBI patients (N = 97, age μ = 41 y; σ = 19 y, range: 21-79) both acutely and chronically (~1 week and ~6 months post-injury, respectively), from AD patients (N = 80, age μ = 76 y; σ = 8 y, range: 55-88), and from cognitively normal (CN) adults (N = 78, age μ = 75 y; σ = 5 y, range: 12-90). AD and CN subjects’ data were acquired less than a year apart. MRIs were analyzed using 3DSlicer’s BRAINSfit (registration), FreeSurfer (segmentation), SPM12 (bias field correction) and custom MATLAB scripts to calculate myelin content and demyelination. The null hypothesis of no myelin change was tested at each cortical location for each pair of groups (α = 0.05), after accounting for age, sex and interscan interval. Compared to HCs, AD subjects featured significantly greater myelin loss in dorsolateral prefrontal cortex, lateral and medial temporal lobes (~52% of the cortex, p &lt; 0.05). mTBI participants experienced significantly greater myelin loss across ~96% of the cortex (p &lt; 0.05), suggesting that mTBI has dramatic impact upon cortical myelin content. Myelin loss magnitude was comparable across mTBI and AD, particularly within temporal lobes. Future research should study whether post-traumatic demyelination increases the AD risk.

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