Large animal models of traumatic brain injury

Dai, Junxi; Ma, Yu‐Lan; Le, Nanyang; Cao, Jun; Wang, Yang

doi:10.1080/00207454.2017.1380008

Cited by 39 publications

(27 citation statements)

References 118 publications

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“…The vast majority (~ 95%) of patients suffer a mild TBI (mTBI) with Glasgow Come Scale (GCS) scores of 13–15 3 , 4 which, contrary to common perception, cause structural sequelae with variable degrees of injury to neurons, glia, and vascular structures, leading to a spectrum of potential clinical outcomes. As translatability is a primary focus of neurotrauma research, there has been a call for use of higher-order gyrencephalic animal models prior to transitioning to the clinic 5 – 9 , however, knowledge regarding the TBI-induced pathophysiology in higher order animal models is still limited. Operation Brain Trauma Therapy (OBTT) is a drug- and biomarker-screening consortium intended to address barriers in the translation from preclinical to clinical studies in TBI by improving the quality of preclinical studies and providing a rigorous framework to increase the translational potential of experimental TBI treatments.…”

Section: Introductionmentioning

confidence: 99%

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

Lafrenaye

Mondello

Wang

et al. 2020

Sci Rep

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Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (tBi). However, their relationship with diffuse histopathology remains unclear. Additionally, translatability is a focus of neurotrauma research, however, studies using translational animal models are limited. Here, we evaluated associations between circulating biomarkers and acute thalamic histopathology in a translational micro pig model of mTBI. Serum samples were collected pre-injury, and 1 min-6 h following mTBI. Markers of neuronal injury (Ubiquitin Carboxy-terminal Hydrolase L1 [UCH-L1]), microglial/macrophage activation (Ionized calcium binding adaptor molecule-1 [Iba-1]) and interleukin-6 [IL-6]) and astrogliosis/astrocyte damage (glial fibrillary acidic protein [GFAP]) were measured. Axonal injury and histological features of neurons and glia were also investigated using immunofluorescent labeling and correlated to serum levels of the associated biomarkers. Consistent with prior experimental and human studies, GFAP, was highest at 6 h post-injury, while no substantial changes were observed in UCH-L1, Iba-1 or IL-6 over 6 h. This study also found promising associations between thalamic glial histological signatures and ensuing release of Iba-1 and GFAP into the circulation. Our findings suggest that in diffuse injury, monitoring serum Iba-1 and GFAP levels can provide clinically relevant insight into the underlying acute pathophysiology and biomarker release kinetics following mTBI, providing previously underappreciated diagnostic capability. Traumatic brain injury (TBI) is an increasing challenge and a global health priority 1 , with more than 50 million TBIs occurring worldwide each year with an associated cost of approximately $400 billion 2. The vast majority (~ 95%) of patients suffer a mild TBI (mTBI) with Glasgow Come Scale (GCS) scores of 13-15 3,4 which, contrary to common perception, cause structural sequelae with variable degrees of injury to neurons, glia, and vascular structures, leading to a spectrum of potential clinical outcomes. As translatability is a primary focus of neurotrauma research, there has been a call for use of higher-order gyrencephalic animal models prior to transitioning to the clinic 5-9 , however, knowledge regarding the TBI-induced pathophysiology in higher order animal models is still limited. Operation Brain Trauma Therapy (OBTT) is a drug-and biomarker-screening

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Section: Introductionmentioning

confidence: 99%

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

Lafrenaye

Mondello

Wang

et al. 2020

Sci Rep

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“…Due to their particular anatomy and size, sheep (Ovis aries) have been largely used as animal models in a multitude of specialities in biomedical research ranging from orthopaedics(9), traumatic brain injury (10) and neurological disorders (11).…”

Section: Discussionmentioning

confidence: 99%

Morphometric Study of The Ventricular Indexes in Healthy Ovine Brain Using MRI

Trovatelli¹,

Spediacci²,

Castellano³

et al. 2020

Preprint

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BackgroundSheep (Ovis aries) have been largely used as animal models in a multitude of specialties in biomedical research. The similarity to human brain anatomy in terms of brain size, skull features, and gyrification index, gives to ovine as a large animal model a better translational value than small animal models in neuroscience. Despite this evidence and the availability of advanced imaging techniques, morphometric brain studies are lacking. We herein present the morphometric ovine brain indexes and anatomical measures developed by two observers in a double-blinded study and validated via an intra- and inter-observer analysis. ResultsFor this retrospective study, T1-weighted Magnetic Resonance Imaging (MRI) scans were performed at 1.5T on 15 sheep, under general anaesthesia. The animals were female Ovis aries, in the age of 18-24 months. Two observers assessed the scans, twice time each. The statistical analysis of intra-observer and inter-observer agreement was obtained via the Bland-Altman plot and Spearman rank correlation test.The results are as follows (mean±Standard deviation): Indexes: Bifrontal 0,338 ± 0,032 cm; Bicaudate 0,080 ± 0,012 cm; Evans’ 0,218 ± 0,035 cm; Ventricular 0,241 ± 0,039 cm; Huckman 1,693 ± 0,174 cm; Cella Media 0,096 ± 0,037 cm; Third ventricle ratio 0,040 ± 0,007 cm. Anatomical measures: Fourth ventricle length 0,295 ± 0,073 cm; Fourth ventricle width 0,344 ± 0,074 cm; Left lateral ventricle 4,175 ± 0,275 cm; Right lateral ventricle 4,182 ± 0,269 cm; Frontal horn length 1,795 ± 0,303 cm; Interventricular foramen left 1,794 ± 0,301cm; Interventricular foramen right 1,78 ± 0,317 cm.ConclusionsThe present study provides baseline values of linear indexes of the ventricles in the ovine models. The acquisition of these data contributes to filling the knowledge void on important anatomical and morphological features of the sheep brain.

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“…A variety of TBI models have also been developed using ferrets, rabbits, pigs or non-human primates (Dai et al, 2018). Although there are fewer studies using these animals than rodents, they show both rapid changes (apnea, hypertension, elevated intracranial pressure, intracranial bleeds) that is followed by a more delayed gray and white matter injury that is accompanied by a long-lasting inflammatory response (Dai et al, 2018; Vink, 2018). A major advantage of TBI models using larger animals is that they have gyrencephalic brains that better model the mechanical forces that injure the brain after TBI in humans.…”

Section: Are Studies Of Therapeutic Time Window In Animal Models Relementioning

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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Large animal models of traumatic brain injury

Abstract: Large animal models of TBI play crucial role in determining the underlying mechanisms and screening putative therapeutic targets of TBI.

Cited by 39 publications

References 118 publications

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

Morphometric Study of The Ventricular Indexes in Healthy Ovine Brain Using MRI

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

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