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 Neuroprotective Effects Of The Inert Gas Argon Onexperimental Traumatic Brain Injury In Vivo With The Controlled Cortical Impact Model In Mice

2021 ◽  
Author(s):  
Fritz I. Schneider ◽  
Sandro M Krieg ◽  
Ute Lindauer ◽  
Michael Stoffel ◽  
Yu-Mi Ryang
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Neurological Outcome ◽  
Primary Outcome ◽  
Secondary Outcome ◽  
Outcome Parameter ◽  
Neuroprotective Effects

Abstract BACKGROUND: Argon has shown neuroprotective effects after traumatic brain injury (TBI) and cerebral ischemia in vitro and in focal cerebral ischemia in vivo. The purpose of this study is to show if Argon beneficially impacts brain contusion volume (BCV) as the primary outcome parameter as well as secondary outcome parameters such as brain edema, intracranial pressure (ICP), neurological outcome, and cerebral blood flow (CBF) in an in vivo model.METHODS: Subjects were randomly assigned to either argon treatment or room air. After applying controlled cortical impact (CCI) onto the dura with 8 m/s (displacement 1 mm, impact duration 150 ms), treatment was administered by a recovery chamber with 25%, 50%, or 75% argon and the rest being oxygen for 4 h after trauma. Two control groups received room air for 15 min and 24 h, respectively. Neurological testing and ICP measurements were performed 24 h after trauma, and brains were removed to measure secondary brain damage. RESULTS: The primary outcome parameter BCV and the secondary outcome parameter brain edema were not significantly reduced by argon treatment at any concentration, respectively. There was a highly significant decrease in ICP at 50% argon (p=0.001), and significant neurological improvement (beamwalk missteps) at 25% and 50% argon (p=0.01; p=0.049 respectively) compared to control.CONCLUSIONS: Similar to prior in vitro studies argon exerts its best neuroprotective effects with regard to neurological outcome and ICP at a concentration of 50%. Furthermore, a significant improvement in neurological outcome was observed at an argon concentration of 25%. There was no significant reduction of BCV as the primary outcome parameter.

Sestrin2 protects against traumatic brain injury by reinforcing the activation of Nrf2 signaling

2020 ◽  
pp. 096032712098422
Author(s):  
Xiaobin Liu ◽  
Min Li ◽  
Jiabao Zhu ◽  
Weidong Huang ◽  
Jinning Song
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cortical Neurons ◽  
In Vitro Models ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Nuclear Levels

Sestrin2 (SESN2) is stress-inducible protein that confers cytoprotective effects against various noxious stimuli. Accumulating evidence has documented that SESN2 has potent anti-apoptosis and anti-oxidative stress functions. However, whether it provides neuroprotection in traumatic brain injury (TBI) models remains unexplored. The purpose of this study was to explore the regulatory effect of SESN2 on TBI using in vivo and in vitro models. We found that TBI resulted in a marked induction of SESN2 in the cerebral cortex tissues of mice. SESN2 overexpression in the brain by in vivo gene transfer significantly decreased neurological deficit, brain edema, and neuronal apoptosis of mice with TBI. Moreover, the overexpression of SESN2 significantly decreased the oxidative stress induced by TBI in mice. In vitro studies of TBI demonstrated that SESN2 overexpression decreased apoptosis and oxidative stress in scratch-injured cortical neurons. Notably, SESN2 overexpression increased the nuclear levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and enhanced the activation of Nrf2 antioxidant signaling in in vivo and in vitro models of TBI. In addition, the inhibition of Nrf2 significantly abolished SESN2-mediated neuroprotective effects in vivo and in vitro. In conclusion, these results of our work demonstrate that SESN2 protects against TBI by enhancing the activation of Nrf2 antioxidant signaling.

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)

Abstract 15142: Endogenous Cardiac Stem Cells’ Activation in Response to Injury Potentiates Their Regenerative Ability

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Andrew J Smith ◽  
Iolanda Aquila ◽  
Beverley J Henning ◽  
Mariangela Scalise ◽  
Bernardo Nadal-Ginard ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Injury ◽  
Fold Increase ◽  
Cardiac Stem Cells ◽  
Post Injury ◽  
Activated State ◽  
Potential Benefits ◽  
Therapeutic Avenue

The identification of resident, endogenous cardiac stem cells (eCSCs) has re-shaped our understanding of cardiac cellular physiology, while offering a significant potential therapeutic avenue. The biology of these cells must be better understood to harness their potential benefits. We used an acute dose (s.c.; 5mgkg-1) of isoproterenol (ISO) to induce diffuse cardiac injury, with associated eCSC activation, in rats. As peak eCSC activation was at 24 hours post ISO-injury, c-kitpos eCSCs were isolated, characterised and their potential for growth and regenerative potential was assessed in vitro and in vivo, respectively. Activated eCSCs showed increased cell cycling activity (51+1% in S- or G2/M phases vs. 9+2% of quiescent), Ki67 expression (56+7% vs. 10+1%) and TERT expression (14-fold increase vs. quiescent). When directly harvested in culture, activated eCSCs showed augmented proliferation, clonogenicity and cardiosphere formation compared to quiescent eCSCs. Activated eCSCs showed increases in expression of numerous growth factors, particularly HGF, IGF-1, TGF-β, periostin, PDGF-AA and VEGF-A. Furthermore, significant alterations were found in the miRnome, notably increased miR-146b and -221, and decreased miR-192 and -351. ISO+5FU was administrated to mice to induce a model of chronic dilated cardiomyopathy, which is characterized by the ablation of eCSCs and the absence of cardiomyocyte replenishment. In these mice with chronic heart failure, freshly isolated quiescent eCSCs or activated eCSCs (2d post-ISO) were injected through the tail vein. 28 days after injection, activated but not quiescent eCSCs re-populated the resident CSC pool, promoted robust new cardiomyocyte formation and improved cardiac function when compared to saline-treated mice. Dual-labelling with BrdU and EdU at selected stages after ISO injury determined that activated eCSCs returned to a quiescent level by 10 weeks post-injury. In conclusion, CSCs rapidly switch from a quiescent to an activated state to match the myocardial needs for myocyte replacement after injury and then spontaneously go back to quiescence. Harnessing the molecules regulating this process may open up future novel approaches for effective myocardial regeneration.

scholarly journals The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway

2011 ◽  
Vol 29 (4) ◽  
pp. 630-636 ◽  
Author(s):  
TAO CHEN ◽  
LEI ZHANG ◽  
YAN QU ◽  
KAI HUO ◽  
XIAOFAN JIANG ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Akt Pathway

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 Embedded axonal fiber tracts improve finite element model predictions of traumatic brain injury

2019 ◽  
Vol 19 (3) ◽  
pp. 1109-1130 ◽  
Author(s):  
Marzieh Hajiaghamemar ◽  
Taotao Wu ◽  
Matthew B. Panzer ◽  
Susan S. Margulies
Keyword(s):  
Traumatic Brain Injury ◽  
Finite Element ◽  
Brain Injury ◽  
Strain Rate ◽  
Brain Tissue ◽  
Brain Injuries ◽  
Characteristic Curve ◽  
Strain And Strain Rate

AbstractWith the growing rate of traumatic brain injury (TBI), there is an increasing interest in validated tools to predict and prevent brain injuries. Finite element models (FEM) are valuable tools to estimate tissue responses, predict probability of TBI, and guide the development of safety equipment. In this study, we developed and validated an anisotropic pig brain multi-scale FEM by explicitly embedding the axonal tract structures and utilized the model to simulate experimental TBI in piglets undergoing dynamic head rotations. Binary logistic regression, survival analysis with Weibull distribution, and receiver operating characteristic curve analysis, coupled with repeated k-fold cross-validation technique, were used to examine 12 FEM-derived metrics related to axonal/brain tissue strain and strain rate for predicting the presence or absence of traumatic axonal injury (TAI). All 12 metrics performed well in predicting of TAI with prediction accuracy rate of 73–90%. The axonal-based metrics outperformed their rival brain tissue-based metrics in predicting TAI. The best predictors of TAI were maximum axonal strain times strain rate (MASxSR) and its corresponding optimal fraction-based metric (AF-MASxSR7.5) that represents the fraction of axonal fibers exceeding MASxSR of 7.5 s−1. The thresholds compare favorably with tissue tolerances found in in–vitro/in–vivo measurements in the literature. In addition, the damaged volume fractions (DVF) predicted using the axonal-based metrics, especially MASxSR (DVF = 0.05–4.5%), were closer to the actual DVF obtained from histopathology (AIV = 0.02–1.65%) in comparison with the DVF predicted using the brain-related metrics (DVF = 0.11–41.2%). The methods and the results from this study can be used to improve model prediction of TBI in humans.

scholarly journals Administration of a 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor Improves Outcome in a Rat Model of Pediatric Traumatic Brain Injury

2019 ◽  
Vol 41 (3-4) ◽  
pp. 166-176 ◽  
Author(s):  
Shiyu Shu ◽  
Zhi Zhang ◽  
Dawn Spicer ◽  
Ewa Kulikowicz ◽  
Ke Hu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Ischemia Reperfusion ◽  
Memory Task ◽  
Male Rats ◽  
Lesion Volume ◽  
Hydroxyeicosatetraenoic Acid ◽  
Post Injury ◽  
Synthesis Inhibitor ◽  
Tnf Α

The arachidonic acid pathway metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia/reperfusion brain injury. Inhibition of 20-HETE formation can protect the developing brain from global ischemia. Here, we examined whether treatment with the 20-HETE synthesis inhibitor N-hydroxy-N-4-butyl-2-methylphenylformamidine (HET0016) can protect the immature brain from traumatic brain injury (TBI). Male rats at postnatal day 9–10 underwent controlled cortical impact followed by intraperitoneal injection with vehicle or HET0016 (1 mg/kg, 5 min and 3 h post-injury). HET0016 decreased the lesion volume by over 50% at 3 days of recovery, and this effect persisted at 30 days as the brain matured. HET0016 decreased peri-lesion gene expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β]) at 1 day and increased reparative cytokine (IL-4, IL-10) expression at 3 days. It also partially preserved microglial ramified processes, consistent with less activation. HET0016 decreased contralateral hindlimb foot faults and improved outcome on the novel object recognition memory task 30 days after TBI. In cultured BV2 microglia, HET0016 attenuated the lipopolysaccharide-evoked increase in release of TNF-α. Our data show that HET0016 improves acute and long-term histologic and functional outcomes, in association with an attenuated neuroinflammatory response after contusion of an immature rat brain.

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