scholarly journals Interactions among Genetic Background, Anesthetic Agent, and Oxygen Concentration Shape Blunt Traumatic Brain Injury Outcomes in Drosophila melanogaster

2020 ◽  
Vol 21 (18) ◽  
pp. 6926
Author(s):  
Amanda R. Scharenbrock ◽  
Hannah J. Schiffman ◽  
Zachariah P. G. Olufs ◽  
David A. Wassarman ◽  
Misha Perouansky
Keyword(s):  
Traumatic Brain Injury ◽  
Drosophila Melanogaster ◽  
Brain Injury ◽  
Genetic Background ◽  
Time Window ◽  
Fruit Fly ◽  
Therapeutic Interventions ◽  
General Anesthetics ◽  
Secondary Injuries ◽  
Locomotor Impairment

Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration–deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI–induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics.

scholarly journals Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish

Genetics ◽  
2020 ◽  
Vol 216 (4) ◽  
pp. 1117-1136 ◽  
Author(s):  
Laura C. Swanson ◽  
Edna A. Trujillo ◽  
Gene H. Thiede ◽  
Rebeccah J. Katzenberger ◽  
Evgenia Shishkova ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
Innate Immune Response ◽  
Genetic Background ◽  
Cellular Response ◽  
Expression Profiles ◽  
Innate Immune ◽  
Immune Response Genes ◽  
Secondary Injuries

Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by nuclear factor-κB (NF-κB) transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-κB factors Dif and Relish (Rel), respectively. Here, we found by mass spectrometry that Rel protein level increased in fly heads at 4–8 hr after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Reldel, by CRISPR/Cas9 editing. When heterozygous but not homozygous, the Reldel mutation reduced mortality at 24 hr after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygosity for Reldel on mortality was modulated by genetic background and diet. To identify genes that facilitate effects of Reldel on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Reldel, and Reldel/Reldel flies at 4 hr following TBI. Only a few genes changed expression more than twofold in +/Reldel flies relative to +/+ and Reldel/Reldel flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes.

scholarly journals A Pro-social Pill? The Potential of Pharmacological Treatments to Improve Social Outcomes After Pediatric Traumatic Brain Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Bridgette D. Semple ◽  
Ramesh Raghupathi
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Social Behavior ◽  
Early Life ◽  
Brain Injuries ◽  
Time Window ◽  
Therapeutic Interventions ◽  
Future Research ◽  
Clinical Literature ◽  
The Impact

Traumatic brain injury (TBI) is a leading cause of injury-induced disability in young children worldwide, and social behavior impairments in this population are a significant challenge for affected patients and their families. The protracted trajectory of secondary injury processes triggered by a TBI during early life—alongside ongoing developmental maturation—offers an extended time window when therapeutic interventions may yield functional benefits. This mini-review explores the scarce but promising pre-clinical literature to date demonstrating that social behavior impairments after early life brain injuries can be modified by drug therapies. Compounds that provide broad neuroprotection, such as those targeting neuroinflammation, oxidative stress, axonal injury and/or myelination, may prevent social behavior impairments by reducing secondary neuropathology. Alternatively, targeted treatments that promote affiliative behaviors, exemplified by the neuropeptide oxytocin, may reduce the impact of social dysfunction after pediatric TBI. Complementary literature from other early life neurodevelopmental conditions such as hypoxic ischemic encephalopathy also provides avenues for future research in neurotrauma. Knowledge gaps in this emerging field are highlighted throughout, toward the goal of accelerating translational research to support optimal social functioning after a TBI during early childhood.

scholarly journals Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Kazuyuki Miyamoto ◽  
Hirokazu Ohtaki ◽  
Kenji Dohi ◽  
Tomomi Tsumuraya ◽  
Dandan Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Death ◽  
Time Window ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Therapeutic Time Window

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2∙-) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease inO2∙-levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.

scholarly journals Gait Quality Assessment in Survivors from Severe Traumatic Brain Injury: An Instrumented Approach Based on Inertial Sensors

Sensors ◽  
2019 ◽  
Vol 19 (23) ◽  
pp. 5315 ◽  
Author(s):  
Valeria Belluscio ◽  
Elena Bergamini ◽  
Marco Tramontano ◽  
Amaranta Orejel Bustos ◽  
Giulia Allevi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Severe Traumatic Brain Injury ◽  
Inertial Sensors ◽  
Gait Disorders ◽  
Therapeutic Interventions ◽  
Control Group ◽  
Walking Ability ◽  
Clinical Scales ◽  
Gait Quality

Despite existing evidence that gait disorders are a common consequence of severe traumatic brain injury (sTBI), the literature describing gait instability in sTBI survivors is scant. Thus, the present study aims at quantifying gait patterns in sTBI through wearable inertial sensors and investigating the association of sensor-based gait quality indices with the scores of commonly administered clinical scales. Twenty healthy adults (control group, CG) and 20 people who suffered from a sTBI were recruited. The Berg balance scale, community balance and mobility scale, and dynamic gait index (DGI) were administered to sTBI participants, who were further divided into two subgroups, severe and very severe, according to their score in the DGI. Participants performed the 10 m walk, the Figure-of-8 walk, and the Fukuda stepping tests, while wearing five inertial sensors. Significant differences were found among the three groups, discriminating not only between CG and sTBI, but also for walking ability levels. Several indices displayed a significant correlation with clinical scales scores, especially in the 10 m walking and Figure-of-8 walk tests. Results show that the use of wearable sensors allows the obtainment of quantitative information about a patient’s gait disorders and discrimination between different levels of walking abilities, supporting the rehabilitative staff in designing tailored therapeutic interventions.

scholarly journals Chronic gliosis and behavioral deficits in mice following repetitive mild traumatic brain injury

2014 ◽  
Vol 121 (6) ◽  
pp. 1342-1350 ◽  
Author(s):  
Rebekah Mannix ◽  
Jacqueline Berglass ◽  
Justin Berkner ◽  
Philippe Moleus ◽  
Jianhua Qiu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Spatial Memory ◽  
Mild Traumatic Brain Injury ◽  
Exploratory Behavior ◽  
Clinical Syndrome ◽  
Therapeutic Interventions ◽  
Behavioral Testing ◽  
Behavioral Deficits ◽  
Structural Brain Damage

Object With the recent increasing interest in outcomes after repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions), several models of rmTBI have been established. Characterizing these models in terms of behavioral and histopathological outcomes is vital to assess their clinical translatability. The purpose of this study is to provide an in-depth behavioral and histopathological phenotype of a clinically relevant model of rmTBI. Methods The authors used a previously published weight-drop model of rmTBI (7 injuries in 9 days) in 2- to 3-month-old mice that produces cognitive deficits without persistent loss of consciousness, seizures, gross structural imaging findings, or microscopic evidence of structural brain damage. Injured and sham-injured (anesthesia only) mice were subjected to a battery of behavioral testing, including tests of balance (rotarod), spatial memory (Morris water maze), anxiety (open field plus maze), and exploratory behavior (hole-board test). After behavioral testing, brains were assessed for histopathological outcomes, including brain volume and microglial and astrocyte immunolabeling. Results Compared with sham-injured mice, mice subjected to rmTBI showed increased exploratory behavior and had impaired balance and worse spatial memory that persisted up to 3 months after injury. Long-term behavioral deficits were associated with chronic increased astrocytosis and microgliosis but no volume changes. Conclusions The authors demonstrate that their rmTBI model results in a characteristic behavioral phenotype that correlates with the clinical syndrome of concussion and repetitive concussion. This model offers a platform from which to study therapeutic interventions for rmTBI.

scholarly journals Loss of highwire Protects Against the Deleterious Effects of Traumatic Brain Injury in Drosophila Melanogaster

2020 ◽  
Vol 11 ◽  
Author(s):  
Ciaran S. Hill ◽  
Jemeen Sreedharan ◽  
Andrea Loreto ◽  
David K. Menon ◽  
Michael P. Coleman
Keyword(s):  
Traumatic Brain Injury ◽  
Drosophila Melanogaster ◽  
Brain Injury

scholarly journals Effects of concussion on the blood–brain barrier in humans and rodents

2017 ◽  
Vol 1 ◽  
pp. 205970021668451 ◽  
Author(s):  
Ronald Sahyouni ◽  
Paula Gutierrez ◽  
Eric Gold ◽  
Richard T Robertson ◽  
Brian J Cummings
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Blood Brain Barrier ◽  
Time Course ◽  
Time Window ◽  
The United States ◽  
Model Systems ◽  
Brain Barrier ◽  
Tracer Injection ◽  
Blood Brain

Traumatic brain injury and the long-term consequences of repeated concussions constitute mounting concerns in the United States, with 5.3 million individuals living with a traumatic brain injury-related disability. Attempts to understand mechanisms and possible therapeutic approaches to alleviate the consequences of repeat mild concussions or traumatic brain injury on cerebral vasculature depend on several aspects of the trauma, including: (1) the physical characteristics of trauma or insult that result in damage; (2) the time “window” after trauma in which neuropathological features develop; (3) methods to detect possible breakdown of the blood–brain barrier; and (4) understanding different consequences of a single concussion as compared with multiple concussions. We review the literature to summarize the current understanding of blood–brain barrier and endothelial cell changes post-neurotrauma in concussions and mild traumatic brain injury. Attention is focused on concussion and traumatic brain injury in humans, with a goal of pointing out the gaps in our knowledge and how studies of rodent model systems of concussion may help in filling these gaps. Specifically, we focus on disruptions that concussion causes to the blood–brain barrier and its multifaceted consequences. Importantly, the magnitude of post-concussion blood–brain barrier dysfunction may influence the time course and extent of neuronal recovery; hence, we include in this review comparisons of more severe traumatic brain injury to concussion where appropriate. Finally, we address the important, and still unresolved, issue of how best to detect possible breakdown in the blood–brain barrier following neurotrauma by exploring intravascular tracer injection in animal models to examine leakage into the brain parenchyma.

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