Animal models of traumatic brain injury
TL;DR: There is a compelling need to revisit the current status of animal models of TBI and therapeutic strategies, as promising neuroprotective drugs identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials.
Abstract: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.
Citations
More filters
TL;DR: Using network analysis of DTI data from healthy volunteers, and meta-analyses of published MRI studies in 26 brain disorders, Crossley et al. show that lesions across disorders tend to be concentrated at hubs.
Abstract: Brain networks or 'connectomes' include a minority of highly connected hub nodes that are functionally valuable, because their topological centrality supports integrative processing and adaptive behaviours. Recent studies also suggest that hubs have higher metabolic demands and longer-distance connections than other brain regions, and therefore could be considered biologically costly. Assuming that hubs thus normally combine both high topological value and high biological cost, we predicted that pathological brain lesions would be concentrated in hub regions. To test this general hypothesis, we first identified the hubs of brain anatomical networks estimated from diffusion tensor imaging data on healthy volunteers (n = 56), and showed that computational attacks targeted on hubs disproportionally degraded the efficiency of brain networks compared to random attacks. We then prepared grey matter lesion maps, based on meta-analyses of published magnetic resonance imaging data on more than 20 000 subjects and 26 different brain disorders. Magnetic resonance imaging lesions that were common across all brain disorders were more likely to be located in hubs of the normal brain connectome (P < 10(-4), permutation test). Specifically, nine brain disorders had lesions that were significantly more likely to be located in hubs (P < 0.05, permutation test), including schizophrenia and Alzheimer's disease. Both these disorders had significantly hub-concentrated lesion distributions, although (almost completely) distinct subsets of cortical hubs were lesioned in each disorder: temporal lobe hubs specifically were associated with higher lesion probability in Alzheimer's disease, whereas in schizophrenia lesions were concentrated in both frontal and temporal cortical hubs. These results linking pathological lesions to the topological centrality of nodes in the normal diffusion tensor imaging connectome were generally replicated when hubs were defined instead by the meta-analysis of more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders.
978 citations
Cites background from "Animal models of traumatic brain in..."
...brain injury (Xiong et al., 2013) or multiple sclerosis (Ransohoff,...
[...]
...Experimental lesions in animals caused by global hypoxia, mitochondrial dysfunction (Melov, 2004), or diffuse axonal injury as seen in models of traumatic brain injury (Xiong et al., 2013) or multiple sclerosis (Ransohoff, 2012), could be revisited within this framework....
[...]
TL;DR: The purpose of this review is to distinguish different variations of neuro inflammation in a context‐specific manner and detail both positive and negative aspects of neuroinflammatory processes.
Abstract: There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as 'neuroinflammatory'. Aspects of neuroinflammation vary within the context of disease, injury, infection, or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical, and behavioral consequences. Microglia, innate immune cells of the CNS, play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context-specific manner and detail both positive and negative aspects of neuroinflammatory processes. In this review, we will use brain and spinal cord injury, stress, aging, and other inflammatory events to illustrate the potential harm and benefits inherent to neuroinflammation. Context, course, and duration of the inflammation are highly important to the interpretation of these events, and we aim to provide insight into this by detailing several commonly studied insults. This article is part of the 60th anniversary supplemental issue.
787 citations
TL;DR: A new framework of targeted immunomodulation after TBI is proposed that incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options and highlights findings that could offer novel therapeutic targets for translational and clinical research.
Abstract: The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI - from initial triggers to chronic neuroinflammation - we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.
619 citations
TL;DR: It is demonstrated for the first time that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and by reducing inflammation in rats after TBI.
Abstract: OBJECT Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). In this study the authors tested a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI. METHODS Two groups of 8 Wistar rats were subjected to TBI, followed 24 hours later by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle (phosphate-buffered saline). A third group of 8 rats was used as sham-injured, sham-treated controls. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, modified Neurological Severity Score, and foot-fault tests were performed. Animals were killed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. RESULT...
519 citations
TL;DR: Evidence regarding astrocyte contribution to post-traumatic tissue repair and synaptic remodeling is examined, and the potential for targeting specific aspects of astrogliosis to ameliorate TBI sequelae is considered.
514 citations
Cites background from "Animal models of traumatic brain in..."
...In-depth analysis of the most common models and their utility for investigating specific features of TBI pathology has been the focus of excellent review articles (Xiong et al., 2013)....
[...]
References
More filters
TL;DR: An overview of the epidemiology and impact of TBI is presented, which shows that the number of Americans living with TBI-related disability and their efforts to return to a full and productive life are increasing.
Abstract: Traumatic brain injury (TBI) is an important public health problem in the United States and worldwide. The estimated 5.3 million Americans living with TBI-related disability face numerous challenges in their efforts to return to a full and productive life. This article presents an overview of the epidemiology and impact of TBI. Language: en
3,554 citations
TL;DR: New developments and current knowledge and controversies, focusing on moderate and severe TBI in adults, are summarised, with an emphasis on epidemiological monitoring, trauma organisation, and approaches to management.
Abstract: Traumatic brain injury (TBI) is a major health and socioeconomic problem that affects all societies. In recent years, patterns of injury have been changing, with more injuries, particularly contusions, occurring in older patients. Blast injuries have been identified as a novel entity with specific characteristics. Traditional approaches to the classification of clinical severity are the subject of debate owing to the widespread policy of early sedation and ventilation in more severely injured patients, and are being supplemented with structural and functional neuroimaging. Basic science research has greatly advanced our knowledge of the mechanisms involved in secondary damage, creating opportunities for medical intervention and targeted therapies; however, translating this research into patient benefit remains a challenge. Clinical management has become much more structured and evidence based since the publication of guidelines covering many aspects of care. In this Review, we summarise new developments and current knowledge and controversies, focusing on moderate and severe TBI in adults. Suggestions are provided for the way forward, with an emphasis on epidemiological monitoring, trauma organisation, and approaches to management.
1,863 citations
TL;DR: There is a large gap in data on incidence, risk factors, sequelae, financial costs, and social impact of TBI, and this should be addressed through planning of comprehensive TBI prevention programs in LMICs through well-established surveillance systems.
Abstract: Traumatic brain injury (TBI), according to the World Health Organization, will surpass many diseases as the major cause of death and disability by the year 2020. With an estimated 10 million people affected annually by TBI, the burden of mortality and morbidity that this condition imposes on society, makes TBI a pressing public health and medical problem. The burden of TBI is manifest throughout the world, and is especially prominent in Low and Middle Income Countries which face a higher preponderance of risk factors for causes of TBI and have inadequately prepared health systems to address the associated health outcomes. Latin America and Sub Saharan Africa demonstrate a higher TBI-related incidence rate varying from 150-170 per 100,000 respectively due to RTIs compared to a global rate of 106 per 100,000. As highlighted in this global review of TBI, there is a large gap in data on incidence, risk factors, sequelae, financial costs, and social impact of TBI. This should be addressed through planning of comprehensive TBI prevention programs in LMICs through well-established surveillance systems. Greater resources for research and prioritized interventions are critical to promote evidence-based policy for TBI.
1,541 citations
TL;DR: Intravenously administered HUCBC enter brain, survive, migrate, and improve functional recovery after stroke in rats, and may provide a cell source to treat stroke.
Abstract: Background and Purpose— Human umbilical cord blood cells (HUCBC) are rich in stem and progenitor cells. In this study we tested whether intravenously infused HUCBC enter brain, survive, differentiate, and improve neurological functional recovery after stroke in rats. In addition, we tested whether ischemic brain tissue extract selectively induces chemotaxis of HUCBC in vitro. Methods— Adult male Wistar rats were subjected to transient (2-hour) middle cerebral artery occlusion (MCAO). Experimental groups were as follows: group 1, MCAO alone (n=5); group 2, 3×106 HUCBC injected into tail vein at 24 hours after MCAO (n=6) (animals of groups 1 and 2 were killed at 14 days after MCAO); group 3, MCAO alone (n=5); group 4, MCAO injected with PBS at 1 day after stroke (n=8); and group 5, 3×106 HUCBC injected into tail vein at 7 days after MCAO (n=5). Rats of groups 3, 4, and 5 were killed at 35 days after MCAO. Behavioral tests (rotarod and Modified Neurological Severity Score [mNSS]) were performed. Immunohistoc...
1,205 citations
TL;DR: It is concluded that this simple model is capable of producing a graded brain injury in the rodent without a massive hypertensive surge or excessive brain-stem damage.
Abstract: This report describes the development of an experimental head injury model capable of producing diffuse brain injury in the rodent. A total of 161 anesthetized adult rats were injured utilizing a simple weight-drop device consisting of a segmented brass weight free-falling through a Plexiglas guide tube. Skull fracture was prevented by cementing a small stainless-steel disc on the calvaria. Two groups of rats were tested: Group 1, consisting of 54 rats, to establish fracture threshold; and Group 2, consisting of 107 animals, to determine the primary cause of death at severe injury levels. Data from Group 1 animals showed that a 450-gm weight falling from a 2-m height (0.9 kg-m) resulted in a mortality rate of 44% with a low incidence (12.5%) of skull fracture. Impact was followed by apnea, convulsions, and moderate hypertension. The surviving rats developed decortication flexion deformity of the forelimbs, with behavioral depression and loss of muscle tone. Data from Group 2 animals suggested that the cause of death was due to central respiratory depression; the mortality rate decreased markedly in animals mechanically ventilated during the impact. Analysis of mathematical models showed that this mass-height combination resulted in a brain acceleration of 900 G and a brain compression gradient of 0.28 mm. It is concluded that this simple model is capable of producing a graded brain injury in the rodent without a massive hypertensive surge or excessive brain-stem damage.
1,193 citations