Traumatic brain injury, a leading cause of death and disability, is a result of an outside force causing mechanical disruption of brain tissue and delayed pathogenic events which collectively exacerbate the injury. These pathogenic injury processes are poorly understood and accordingly no effective neuroprotective treatment is available so far. Experimental models are essential for further clarification of the highly complex pathology of traumatic brain injury towards the development of novel treatments. Among the rodent models of traumatic brain injury the most commonly used are the weight-drop, the fluid percussion, and the cortical contusion injury models. As the entire spectrum of events that might occur in traumatic brain injury cannot be covered by one single rodent model, the design and choice of a specific model represents a major challenge for neuroscientists. This review summarizes and evaluates the strengths and weaknesses of the currently available rodent models for traumatic brain injury.

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Experimental traumatic brain injury

In this study, we investigated the development of endoplasmic reticulum (ER) stress after traumatic brain injury (TBI) and the efficacy of post-TBI administration of docosahexaenoic acid (DHA) in reducing ER stress. TBI was induced by cortical contusion injury in Sprague-Dawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered intraperitoneally at 5 min after TBI, followed by a daily dose for 3–21 d. TBI triggered sustained expression of the ER stress marker proteins including phosphorylated eukaryotic initiation factor-2α, activating transcription factor 4, inositol requiring kinase 1, and C/EBP homologous protein in the ipsilateral cortex at 3–21 d after TBI. The prolonged ER stress was accompanied with an accumulation of abnormal ubiquitin aggregates and increased expression of amyloid precursor protein (APP) and phosphorylated tau (p-Tau) in the frontal cortex after TBI. The ER stress marker proteins were colocalized with APP accumulation in the soma. Interestingly, administration of DHA attenuated all ER stress marker proteins and reduced the accumulation of both ubiquitinated proteins and APP/p-Tau proteins. In addition, the DHA-treated animals exhibited early recovery of their sensorimotor function after TBI. In summary, our study demonstrated that TBI induces a prolonged ER stress, which is positively correlated with abnormal APP accumulation. The sustained ER stress may play a role in chronic neuronal damage after TBI. Our findings illustrate that post-TBI administration of DHA has therapeutic potentials in reducing ER stress, abnormal protein accumulation, and neurological deficits.

https://www.jneurosci.org/content/jneuro/34/10/3743.full.pdf

Docosahexaenoic acid reduces ER stress and abnormal protein accumulation and improves neuronal function following traumatic brain injury.

Scriptaid, a novel histone deacetylase inhibitor, protects against traumatic brain injury via modulation of PTEN and AKT pathway : scriptaid protects against TBI via AKT.

Time-dependent changes of protein biomarkers in the cerebrospinal fluid (CSF) can be used to identify the pathological processes in traumatic brain injury (TBI) as well as to follow the progression of the disease. We obtained CSF from a large animal model (swine) of blast-induced traumatic brain injury prior to and at 6, 24, 72 h, and 2 wk after a single exposure to blast overpressure, and determined changes in the CSF levels of neurofilament-heavy chain, neuron-specific enolase, brain-specific creatine kinase, glial fibrillary acidic protein, calcium-binding protein β (S100β), Claudin-5, vascular endothelial growth factor, and von Willebrand factor using reverse phase protein microarray. We detected biphasic temporal patterns in the CSF concentrations of all tested protein markers except S100β. The CSF levels of all markers were significantly increased 6 h after the injury compared to preinjury levels. Values were then decreased at 24 h, prior to a second increase in all markers but S100β at 72 h. At 2 wk postinjury, the CSF concentrations of all biomarkers were decreased once again; brain-specific creatine kinase, Claudin-5, von Willebrand factor, and S100β levels were no longer significantly higher than their preinjury values while neurofilament-heavy chain, neuron-specific enolase, vascular endothelial growth factor, and glial fibrillary acidic protein levels remained significantly elevated compared to baseline. Our findings implicate neuronal and glial cell damage, compromised vascular permeability, and inflammation in blast-induced traumatic brain injury, as well as demonstrate the value of determining the temporal pattern of biomarker changes that may be of diagnostic value.

Time dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury

BACKGROUNDThe beta-lactam antibiotic, ceftriaxone (CTX), has been reported to induce neuroprotection in animal models of diverse neurologic diseases. Currently, no data have explored the potential for CTX to provide neuroprotection in the animal models of traumatic brain injury (TBI). The aim of thi

The beta-lactam antibiotic, ceftriaxone, provides neuroprotective potential via anti-excitotoxicity and anti-inflammation response in a rat model of traumatic brain injury

Objective – To review current information regarding the pathophysiology associated with traumatic brain injury (TBI), and to outline appropriate patient assessment, diagnostic, and therapeutic options.

Etiology – TBI in veterinary patients can occur subsequent to trauma induced by motor vehicle accidents, falls, and crush injuries. Primary brain injury occurs at the time of initial impact as a result of direct mechanical damage. Secondary brain injury occurs in the minutes to days following the trauma as a result of systemic extracranial events and intracranial changes.

Diagnosis – The initial diagnosis is often made based on history and physical examination. Assessment should focus on the cardiovascular and respiratory systems followed by a complete neurologic examination. Advanced imaging may be indicated in a patient that fails to respond to appropriate medical therapy.

Therapy – Primary brain injury is beyond the control of the veterinarian. Therefore, treatment should focus on minimizing the incidence or impact of secondary brain injury. Because of a lack of prospective or retrospective clinical data, treatment recommendations for veterinary TBI patients are primarily based on human and experimental studies and personal experience. Therapeutic guidelines have been developed that center on maintaining adequate cerebral perfusion.

Prognosis – Severe head trauma is associated with high mortality in humans and animals. However, dogs and cats have a remarkable ability to compensate for loss of cerebral tissue. It is therefore important not to reach hasty prognostic conclusions based on initial appearance. Many pets go on to have a functional outcome and recover from injury.

/pdf/traumatic-brain-injury-a-review-of-pathophysiology-and-4eyczoyx77.pdf

Chad West

Papers

Traumatic brain injury: a review of pathophysiology and management