A stereotaxic atlas of the rat brain

https://researchonline.jcu.edu.au/5134/1/5134_McAfoose_and_Baune_2009.pdf

Evidence for a cytokine model of cognitive function

Traumatic brain injury (TBI) is a significant problem in older adults. In persons aged 65 and older, TBI is responsible for more than 80,000 emergency department visits each year; three-quarters of these visits result in hospitalization as a result of the injury. Adults aged 75 and older have the highest rates of TBI-related hospitalization and death. Falls are the leading cause of TBI for older adults (51%), and motor vehicle traffic crashes are second (9%). Older age is known to negatively influence outcome after TBI. Although geriatric and neurotrauma investigators have identified the prognostic significance of preadmission functional ability, comorbidities, sex, and other factors such as cerebral perfusion pressure on recovery after illness or injury, these variables remain understudied in older adults with TBI. In the absence of good clinical data, predicting outcomes and providing care in the older adult population with TBI remains problematic. To address this significant public health issue, a refocusing of research efforts on this population is justified to prevent TBI in the older adult and to discern unique care requirements to facilitate best patient outcomes.

/pdf/traumatic-brain-injury-in-older-adults-epidemiology-outcomes-30hybhd44f.pdf

Traumatic Brain Injury in Older Adults: Epidemiology, Outcomes, and Future Implications

This article comprehensively reviews the lateral fluid percussion (LFP) model of traumatic brain injury (TBI) in small animal species with particular emphasis on its validity, clinical relevance and reliability. The LFP model, initially described in 1989, has become the most extensively utilized animal model of TBI (to date, 232 PubMed citations), producing both focal and diffuse (mixed) brain injury. Despite subtle variations in injury parameters between laboratories, universal findings are evident across studies, including histological, physiological, metabolic, and behavioral changes that serve to increase the reliability of the model. Moreover, demonstrable histological damage and severity-dependent behavioral deficits, which partially recover over time, validate LFP as a clinically-relevant model of human TBI. The LFP model, also has been used extensively to evaluate potential therapeutic interventions, including resuscitation, pharmacologic therapies, transplantation, and other neuroprotective and neuroregenerative strategies. Although a number of positive studies have identified promising therapies for moderate TBI, the predictive validity of the model may be compromised when findings are translated to severely injured patients. Recently, the clinical relevance of LFP has been enhanced by combining the injury with secondary insults, as well as broadening studies to incorporate issues of gender and age to better approximate the range of human TBI within study design. We conclude that the LFP brain injury model is an appropriate tool to study the cellular and mechanistic aspects of human TBI that cannot be addressed in the clinical setting, as well as for the development and characterization of novel therapeutic interventions. Continued translation of pre-clinical findings to human TBI will enhance the predictive validity of the LFP model, and allow novel neuroprotective and neuroregenerative treatment strategies developed in the laboratory to reach the appropriate TBI patients.

Lateral fluid percussion brain injury: a 15-year review and evaluation.

https://journals.sagepub.com/doi/pdf/10.1177/0963689717714102

Traumatic Brain Injury: Current Treatment Strategies and Future Endeavors

The NTera2 (NT2) cell line is a homogeneous population of cells, which, when treated in vitro with retinoic acid, terminally differentiate into postmitotic neuronal NT2N cells. Although NT2N neurons transplanted in the acute (24 h postinjury) period survive for up to 1 month following experimental traumatic brain injury (TBI), nothing is known of their ability to survive for longer periods or of their effects when engrafted during the chronic postinjury period. Adult male Sprague-Dawley rats (n = 348; 360-400 g) were initially anesthetized and subjected to severe lateral fluid-percussion (FP) brain injury or sham injury. At 1 month postinjury, only brain-injured animals showing severe neurobehavioral deficits received cryopreserved NT2N neurons stereotaxically transplanted into three sites in the peri-injured cortex (n = 18). Separate groups of similarly brain-injured rats received human fibroblast cells (n = 13) or cell suspension vehicle (n = 14). Sham-injured animals (no brain injury) served as controls and received NT2N transplants (n = 24). All animals received daily immunosuppression for three months. Behavioral testing was performed at 1, 4, 8, and 12 weeks post-transplantation, after which animals were sacrificed for histological analysis. Nissl staining and anti-human neuronal specific enolase (NSE) immunostaining revealed that NT2N neurons transplanted in the chronic post-injury period survived up to 12 weeks post-transplantation, extended processes into the host cortex and immunolabeled positively for synaptophysin. There were no statistical differences in cognitive or motor function among the transplanted brain-injured groups. Long-term graft survival suggests that NT2N neurons may be a viable source of neural cells for transplantation after TBI and also that these grafts can survive for a prolonged time and extend processes into the host cortex when transplanted in the chronic post-injury period following TBI.

Delayed transplantation of human neurons following brain injury in rats: a long-term graft survival and behavior study.

PURPOSE: Although many previous studies have indicated that the acute inflammatory response following traumatic brain injury (TBI) is detrimental, inflammation may also positively influence outcome in the more chronic post-injury recovery period. We evaluated the effects of monoclonal antibodies (mAB), neutralizing either IL-6 (IL-6 mAB) or TNF-alpha (TNF mAB), administered intracerebroventricularly (i.c.v) on acute neurobehavioral outcome following TBI.METHODS: Male Sprague-Dawley rats (n = 173) were anesthetized (sodium pentobarbital, 60 mg/kg) and subjected to lateral fluid percussion (FP) brain injury of moderate severity (n = 123) or sham injury (n = 50). Beginning 1 h post-injury, TNF mAB (n = 41, of which 25 were brain-injured) or IL-6 mAB (n = 42, of which 25 were brain-injured) at a concentration of 2 mg/mL was infused i.c.v ipsilateral to the injury for 48 hours. Vehicle-treated animals (control IgG; n = 43, of which 26 were brain-injured) served as controls. In Study 1, cognitive function was evaluated in the Morris Water Maze (MWM) followed by evaluation of regional cerebral edema at 48 h post-injury. In Study 2, animals were evaluated for neurological motor function and post-injury learning in the MWM at one week post-injury.RESULTS: FP brain injury caused significant cognitive (p < 0.05) and neurological motor (p < 0.05) deficits and increased regional brain water content in the injured hemisphere. Treatment with either TNF- or IL-6-mAB had no effect on neurological motor, cognitive function or brain edema during the first post-injury week.CONCLUSIONS: Evaluation of anti-inflammatory mABs on more chronic behavioral deficits appears warranted. (Less)

Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat.

Approximately 50% of severely head-injured patients suffer additional potentially life-threatening extracranial injuries such as multiple fractures, lung contusion, traumatic pneumothorax, and injury to intra-abdominal organs. Despite the high prevalence of multiple trauma in brain-injured patients, only a few studies have investigated the effect of extracranial injuries on the clinical course and outcome of patients with traumatic brain injury (TBI) (1, 2). Nevertheless, the prognosis and outcome have been shown to be worsened when multiple extracranial injuries are involved (1, 3). This exacerbation of injury is believed to be a consequence of secondary insults to the brain resulting from hypoxemia, hypotension, elevated intracranial pressure, insufficient cerebral perfusion pressure, hypercapnia, hyperthermia, hypo/hyperglycemia, hyponatremia, and sepsis (4-6) that can be caused by extracranial traumatic injuries. Although the uninjured brain can normally withstand these secondary insults by activating compensatory mechanisms, the brain is rendered vulnerable to secondary insults due to TBI-induced structural and metabolic deficits. Blood loss and subsequent systemic hypotension are major causes of secondary insult to the brain following TBI and occur more frequently in multiply injured patients (4, 7). Moreover, hypotension in the traumatically injured patient has been shown to be predictive for higher mortality and morbidity rates (8).

Under laboratory conditions, experimentally induced hemorrhagic hypotension (HH) when superimposed on a traumatically injured brain has been shown to impair cerebral perfusion (9, 10) and reduce the amount of oxygen carriers contributing to the already reduced brain tissue oxygenation (11, 12). Additionally, secondary hypotension, with and without concomitant hypoxia, following TBI has been reported to impair systemic pressure autoregulation (13-15), impair cerebral autoregulation (15, 16), and aggravate TBI-induced structural damage as reflected by a significant increase in contusion volume (9, 17-19). Secondary hypoxia has also been reported to exacerbate acute sensorimotor and cognitive deficits following moderate fluid percussion (FP) brain injury in rats (20). To date, most preclinical pathophysiologic and pharmacologic studies have been conducted primarily in animals subjected to isolated TBI without HH, and a strong need exists to develop combined injury models to elucidate optimal treatment and management strategies for multiply-injured patients (see the excellent review in Ref. 21). Although several rodent models of combined injury (TBI with hypoxia, with and without HH) have been established (9, 15, 17, 20, 22, 23), experimental studies investigating the impact of superimposed HH have focused primarily on the pharmacologic restitution of mean arterial blood pressure (MABP) and/or cerebral perfusion pressure by infusing catecholamines (15, 24) and the evaluation of various resuscitation fluids (13, 25, 26). To date, the impact of hemorrhagic hypotension on neurologic and cognitive outcome following TBI has not been investigated.

The present study was designed to reproduce the clinical scenario in which a TBI patient experiences an acute, transient (≤30 mins) arterial hemorrhage immediately following TBI. In one subgroup of brain-injured animals, lactated Ringer’s solution was infused to reverse the arterial hypotension whereas another subgroup was not fluid resuscitated. The impact of superimposed compensated or uncompensated HH on the acute pathologic response to TBI (brain edema formation at 24 hrs postinjury), long-term (5 month) neurobehavioral outcome variables, and hemispheric tissue loss after TBI was also evaluated in the current study.

/pdf/acute-transient-hemorrhagic-hypotension-does-not-aggravate-43anrdh8zp.pdf

Acute, transient hemorrhagic hypotension does not aggravate structural damage or neurologic motor deficits but delays the long-term cognitive recovery following mild to moderate traumatic brain injury.

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Delayed transplantation of human neurons following brain injury in rats: a long-term graft survival and behavior study.

Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat.

Acute, transient hemorrhagic hypotension does not aggravate structural damage or neurologic motor deficits but delays the long-term cognitive recovery following mild to moderate traumatic brain injury.