Righting Reflex Predicts Long-Term Histological and Behavioral Outcomes in a Closed Head Model of Traumatic Brain Injury

Grinkina, Natalia; Yang, Li; Haber, Margalit; Sangobowale, Michael; Nikulina, Elena; Lepre, C; Sehamy, Alexander M. El; Dugue, Rachelle; Ho, Johnson; Bergold, Peter J.

doi:10.1371/journal.pone.0161053

Cited by 32 publications

(48 citation statements)

References 24 publications

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“…CVS). CHI is a closed head model of TBI which avoids the confounds of injuring the brain through a craniotomy (Grin'kina et al, 2016). The CVS model was used to study PTSD.…”

Section: Introductionmentioning

confidence: 99%

Increased Behavioral Deficits and Inflammation in a Mouse Model of Co-Morbid Traumatic Brain Injury and Post-Traumatic Stress Disorder

et al. 2020

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Comorbid post-traumatic stress disorder with traumatic brain injury (TBI) produce more severe affective and cognitive deficits than PTSD or TBI alone. Both PTSD and TBI produce long-lasting neuroinflammation, which may be a key underlying mechanism of the deficits observed in co-morbid TBI/PTSD. We developed a model of co-morbid TBI/PTSD by combining the closed head (CHI) model of TBI with the chronic variable stress (CVS) model of PTSD and examined multiple behavioral and neuroinflammatory outcomes. Male C57/Bl6 mice received sham treatment, CHI, CVS, CHI then CVS (CHI → CVS) or CVS then CHI (CVS → CHI). The CVS → CHI group had deficits in Barnes maze or active place avoidance not seen in the other groups. The CVS → CHI, CVS and CHI → CVS groups displayed increased basal anxiety level, based on performance on elevated plus maze. The CVS → CHI had impaired performance on Barnes Maze, and Active Place Avoidance. These performance deficits were strongly correlated with increased hippocampal Iba-1 level an indication of activated MP/MG. These data suggest that greater cognitive deficits in the CVS → CHI group were due to increased inflammation. The increased deficits and neuroinflammation in the CVS → CHI group suggest that the order by which a subject experiences TBI and PTSD is a major determinant of the outcome of brain injury in co-morbid TBI/PTSD.

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“…CVS). CHI is a closed head model of TBI which avoids the confounds of injuring the brain through a craniotomy (Grin'kina et al, 2016). The CVS model was used to study PTSD.…”

Section: Introductionmentioning

confidence: 99%

Increased Behavioral Deficits and Inflammation in a Mouse Model of Co-Morbid Traumatic Brain Injury and Post-Traumatic Stress Disorder

et al. 2020

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“…3G; SA 2.12). Other methods of securing the head varied in the amount that the head was able to move after injury; this included foam wrapped ear bars, 355 an acrylic or resin mold, 347,363 a plastic collar, 348 a mouse restrainer, 349 or secured vertically from the incisors. 400…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review of Closed Head Injury Models of Mild Traumatic Brain Injury in Mice and Rats

Bodnar

Roberts

Higgins

et al. 2019

Journal of Neurotrauma

130

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Mild TBI (mTBI) is a significant health concern. Animal models of mTBI are essential for understanding mechanisms, and pathological outcomes, as well as to test therapeutic interventions. A variety of closed head models of mTBI that incorporate different aspects (i.e., biomechanics) of the mTBI have been reported. The aim of the current review was to compile a comprehensive list of the closed head mTBI rodent models, along with the common data elements, and outcomes, with the goal to summarize the current state of the field. Publications were identified from a search of PubMed and Web of Science and screened for eligibility following PRISMA guidelines. Articles were included that were closed head injuries in which the authors classified the injury as mild in rats or mice. Injury model and animal-specific common data elements, as well as behavioral and histological outcomes, were collected and compiled from a total of 402 articles. Our results outline the wide variety of methods used to model mTBI. We also discovered that female rodents and both young and aged animals are under-represented in experimental mTBI studies. Our findings will aid in providing context comparing the injury models and provide a starting point for the selection of the most appropriate model of mTBI to address a specific hypothesis. We believe this review will be a useful starting place for determining what has been done and what knowledge is missing in the field to reduce the burden of mTBI.

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“…In most of these models, the impact produces rapid head movements. Permitting head movement more closely models clinical TBI, and produces a more variable injury than models that prevent head movement (Johnson et al, 2015; Grin’kina et al, 2016). Closed head models produce a smaller focal contusion and a more diffuse white matter injury than open head models.…”

Section: Therapeutic Time Windows Differ Depending Upon the Animal Tbmentioning

confidence: 99%

The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury

2019

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Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4–8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing.

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Righting Reflex Predicts Long-Term Histological and Behavioral Outcomes in a Closed Head Model of Traumatic Brain Injury

Cited by 32 publications

References 24 publications

Increased Behavioral Deficits and Inflammation in a Mouse Model of Co-Morbid Traumatic Brain Injury and Post-Traumatic Stress Disorder

Increased Behavioral Deficits and Inflammation in a Mouse Model of Co-Morbid Traumatic Brain Injury and Post-Traumatic Stress Disorder

A Systematic Review of Closed Head Injury Models of Mild Traumatic Brain Injury in Mice and Rats

The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury

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