Long-term potentiation deficits and excitability changes following traumatic brain injury

The effects of traumatic brain injury (TBI) on hippocampal long-term potentiation (LTP) and cellular excitability were assessed at postinjury days 2, 7, and 15. TBI was induced using a well-characterized central fluid-percussion model. LTP of the Schaffer collateral/commissural system was assessed in vivo in urethane-anesthetized rats. Significant LTP of the population excitatory postsynaptic potential (EPSP) slope was found only in controls, and no recovery to control levels was observed for any postinjury time point. Four measurement parameters reflecting pyramidal cell discharges (population spike) indicated that TBI significantly increased cellular excitability at postinjury day 2: (1) pretetanus baseline recording showed that TBI reduced population spike threshold and latency; (2) tetanic stimulation (400 Hz) increased population spike amplitudes to a greater degree in injured animals than in control animals; (3) tetanus-induced population spike latency shifts were greater in injured cases; and (4) tetanic stimulation elevated EPSP to spike ratios (E-S potentiation) to a greater degree in injured animals. These parameters returned to control levels, as measured on postinjury days 7 and 15. These results suggest that TBI-induced excitability changes persist at least through 2 days postinjury and involve a differential impairment of mechanisms subserving LTP of synaptic efficacy and mechanisms related to action potential generation     

Inhibition of cyclooxygenase 2 by nimesulide improves cognitive outcome more than motor outcome following diffuse traumatic brain injury in rats

Prostanoid synthesis is regulated by the enzyme cyclo-oxygenase (COX) that is present in at least two isoforms: COX-1, the constitutive form, and COX-2, the inducible form. Expression of COX-2 has recently been shown to be an important determinant of the cytotoxicity connected with inflammation following ischemic injury to the brain. The present study examines the temporal and spatial profiles of COX-2 expression following diffuse traumatic brain injury (TBI) in rats, and the effects of the COX-2 inhibitor nimesulide on cognitive and motor outcomes. Adult, male Sprague-Dawley rats were injured using the 2-meter impact acceleration model of diffuse TBI. At preselected time points after injury, animals were killed and the expression of COX-2 was measured in the hippocampus and parietal cortex by immunohistochemistry and Western blotting techniques. Effects of nimesulide (6 mg/kg daily over ten days) on cognitive and motor outcome was assessed in a separate group of animals using the Barnes circular maze and rotarod test, respectively. A highly significant up-regulation of COX-2 expression was found in the hippocampus as early as 3 h post-trauma and persisting for at least 12 days after TBI. In contrast, a slight but significant upregulation of COX-2 expression occurred in the cortex only at 3 days after trauma. Administration of the COX-2 inhibitor nimesulide resulted in a significant and substantial improvement in cognitive function compared to vehicle-treated controls, while motor deficits after injury was only improved at 24 h after injury. We conclude that COX-2 is involved in the development of functional deficits following diffuse TBI, particularly cognitive deficits, and that these can be improved by administration of COX-2 inhibitors. Electronic Publication     

Morphine protects for head trauma induced cognitive deficits in mice

Victims of minor traumatic brain injury (mTBI) can show long lasting cognitive, emotional and concentration difficulties, amnesia, depression, apathy and anxiety. The symptoms are generally known as a post-concussive syndrome without clear morphological brain defects. Endogenous opiates are released after impact to the brain, suggesting they may play a role in TBI pathophysiology. Furthermore, the administration of opiates to the brain of injured animals has been shown to affect the injury, induce cellular changes and also have protective qualities for neurological impairments. Here, we examined the protective properties of the opiate morphine on cognitive performances following minimal brain injury in mice. For this purpose, we have used our non-invasive closed-head weight drop model in mice, which closely mimics real life mTBI and examined mice performance in the Morris water maze. Our procedure did not cause visible structural or neurological damage to the mice. A single morphine injection administrated immediately after the induction of minimal TBI protected the injured mice from cognitive impairment, checked 30, 60 and 90 days post injury. However, mice injected with morphine that were examined 7 days after the injury did not show better performance than the saline injected mice. Our results indicate that morphine has long but not short-term effects on the cognitive ability of brain-injured mice. Although the exact nature of opioid neuroprotection is still unknown, its elucidation may lead to the much-needed treatment for traumatic brain injury.     

Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function

Voluntary exercise leads to an upregulation of brain-derived neurotrophic factor (BDNF) and associated proteins involved in synaptic function. Activity-induced enhancement of neuroplasticity may be considered for the treatment of traumatic brain injury (TBI). Given that during the first postinjury week the brain is undergoing dynamic restorative processes and energetic changes that may influence the outcome of exercise, we evaluated the effects of acute and delayed exercise following experimental TBI. Male Sprague-Dawley rats underwent either sham or lateral fluid-percussion injury (FPI) and were housed with or without access to a running wheel (RW) from postinjury days 0-6 (acute) or 14-20 (delayed). FPI alone resulted in significantly elevated levels of hippocampal phosphorylated synapsin I and phosphorylated cyclic AMP response element-binding-protein (CREB) at postinjury day 7, of which phosphorylated CREB remained elevated at postinjury day 21. Sham and delayed FPI-RW rats showed increased levels of BDNF, following exercise. Exercise also increased phosphorylated synapsin I and CREB in sham rats. In contrast to shams, the acutely exercised FPI rats failed to show activity-dependent BDNF upregulation and had significant decreases of phosphorylated synapsin I and total CREB. Additional rats were cognitively assessed (learning acquisition and memory) by utilizing the Morris water maze after acute or delayed RW exposure. Shams and delayed FPI-RW animals benefited from exercise, as indicated by a significant decrease in the number of trials to criterion (ability to locate the platform in 7 s or less for four consecutive trials), compared with the delayed FPI-sedentary rats. In contrast, cognitive performance in the acute FPI-RW rats was significantly impaired compared with all the other groups. These results suggest that voluntary exercise can endogenously upregulate BDNF and enhance recovery when it is delayed after TBI. However, when exercise is administered to soon after TBI, the molecular response to exercise is disrupted and recovery may be delayed.     

透明质酸-半乳糖化壳聚糖复合支架与牛磺酸联合治疗脑创伤大鼠的初步研究

目的 探索透明质酸-半乳糖化壳聚糖复合支架（HGC）联合牛磺酸（Tau）对脑创伤（TBI）大鼠的治疗作用.方法 选择成年SD大鼠40只,随机分为假手术组（Sham组）、脑创伤组（TBI组）、透明质酸-半乳糖化壳聚糖复合支架组（HGC组）、透明质酸-半乳糖化壳聚糖复合支架与牛磺酸联合治疗组（HGC-Tau组）,每组10只.TBI、HGC及HGC-Tau组采用液压打击法在大鼠左侧大脑半球制作TBI模型,Sham组仅在相同位置开骨窗,不予打击.HGC组于造模后7d将30μl HGC植入大鼠脑皮质损伤区,HGC-Tau组以同样方法植入相同体积HGC与牛磺酸的混合物.TBI后1、3、7、10、14、21 d进行改良型神经功能评分（mNSS）,其中17～21 d进行Morris水迷宫（MWM）实验.TBI后28 d采用实时定量PCR及免疫荧光染色检测胶质纤维酸性蛋白质（GFAP）的基因及蛋白表达水平.结果 HGC-Tau组mNSS评分在TBI后14d及21d显著低于TBI组（P＜0.05）,HGC组各时间点评分与TBI组相比,差异均无统计学意义（P＞0.05）,HGC-Tau组与HGC组相比,评分在TBI后14、21 d显著降低（P＜0.05）;HGC-Tau组MWM检测目标象限百分比从创伤后18d开始明显大于TBI组（P＜0.05）,HGC组创伤后21 d目标象限百分比显著大于TBI组（P＜0.05）,HGC-Tau组仅在18、19 d目标象限百分比明显大于HGC组（P＜0.05）;HGC组及HGC-Tau组TBI后28 dGFAP mRNA及蛋白表达量与TBI组相比显著下降（P＜0.05）,且较HGC组,HGC-Tau组下降更加明显（P＜0.05）.结论 单纯使用HGC仅能抑制创伤性脑损伤后胶质细胞增生,对神经功能改善无明显作用.HGC联合Tau治疗可抑制重型脑损伤后胶质细胞增生,改善神经功能,表明生物材料与药物联合治疗脑外伤具有一定的应用前景.     

Delayed sodium pyruvate treatment improves working memory following experimental traumatic brain injury

Prior work indicates that cerebral glycolysis is impaired following traumatic brain injury (TBI) and that pyruvate treatment acutely after TBI can improve cerebral metabolism and is neuroprotective. Since extracellular levels of glucose decrease during periods of increased cognitive demand and exogenous glucose improves cognitive performance, we hypothesized that pyruvate treatment prior to testing could ameliorate cognitive deficits in rats with TBI. Based on pre-surgical spatial alternation performance in a 4-arm plus-maze, adult male rats were randomized to receive either sham injury or unilateral (left) cortical contusion injury (CCI). On days 4, 9 and 14 after surgery animals received an intraperitoneal injection of either vehicle (Sham-Veh, n = 6; CCI-Veh, n = 7) or 1000 mg/kg of sodium pyruvate (CCI-SP, n = 7). One hour after each injection rats were retested for spatial alternation performance. Animals in the CCI-SP group showed no significant working memory deficits in the spatial alternation task compared to Sham-Veh controls. The percent four/five alternation scores for CCI-Veh rats were significantly decreased from Sham-Veh scores on days 4 and 9 (p < 0.01) and from CCI-SP scores on days 4, 9 and 14 (p < 0.05). Measures of cortical contusion volume, regional cerebral metabolic rates of glucose and regional cytochrome oxidase activity at day 15 post-injury did not differ between CCI-SP and CCI-Veh groups. These results show that spatial alternation testing can reliably detect temporal deficits and recovery of working memory after TBI and that delayed pyruvate treatment can ameliorate TBI-induced cognitive impairments.     

Inhibitory effect on cerebral inflammatory agents that accompany traumatic brain injury in a rat model: a potential neuroprotective mechanism of recombinant human erythropoietin (rhEPO)

Erythropoietin (EPO) has recently been shown to have a neuroprotective effect in animal models of traumatic brain injury (TBI). However, the precise mechanisms remain unclear. Cerebral inflammation plays an important role in the pathogenesis of secondary brain injury after TBI. We, therefore, tried to analyze how recombinant human erythropoietin (rhEPO) might effect the inflammation-related factors common to TBI: nuclear factor kappa B (NF-kappaB), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) in a rat TBI model. Male rats were given 0 or 5000 units/kg injections of rhEPO 1h post-injury and on days 1, 2 and 3 after surgery. Brain samples were extracted at 3 days after trauma. We measured NF-kappaB by electrophoretic mobility shift assay (EMSA); IL-1beta, TNF-alpha and IL-6 by enzyme-linked immunosorbent assay (ELISA); ICAM-1 by immunohistochemistry; brain edema by wet/dry method; blood-brain barrier (BBB) permeability by Evans blue extravasation and cortical apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method. We found that NF-kappaB, pro-inflammatory cytokines and ICAM-1 were increased in all injured animals. In animals given rhEPO post-TBI, NF-kappaB, IL-1beta, TNF-alpha and ICAM-1 were decreased in comparison to vehicle-treated animals. Measures of IL-6 showed no change after rhEPO treatment. Administration of rhEPO reduced brain edema, BBB permeability and apoptotic cells in the injured brain. In conclusion, post-TBI rhEPO administration may attenuate inflammatory response in the injured rat brain, and this may be one mechanism by which rhEPO improves outcome following TBI.     

Zinc supplementation provides behavioral resiliency in a rat model of traumatic brain injury

Depression, anxiety, and impairments in learning and memory are all associated with traumatic brain injury (TBI). Because of the strong link between zinc deficiency, depression, and anxiety, in both humans and rodent models, we hypothesized that dietary zinc supplementation prior to injury could provide behavioral resiliency to lessen the severity of these outcomes after TBI. Rats were fed a marginal zinc deficient (5 ppm), zinc adequate (30 ppm), or zinc supplemented (180 ppm) diet for 4 weeks followed by a moderately-severe TBI using the well-established model of controlled cortical impact (CCI). Following CCI, rats displayed depression-like behaviors as measured by the 2-bottle saccharin preference test for anhedonia. Injury also resulted in evidence of stress and impairments in Morris water maze (MWM) performance compared to sham-injured controls. While moderate zinc deficiency did not worsen outcomes following TBI, rats that were fed the zinc supplemented diet for 4 weeks showed significantly attenuated increases in adrenal weight (p < 0.05) as well as reduced depression-like behaviors (p < 0.001). Supplementation prior to injury improved resilience such that there was not only significant improvements in cognitive behavior compared to injured rats fed an adequate diet (p < 0.01), there were no significant differences between supplemented and sham-operated rats in MWM performance at any point in the 10-day trial. These data suggest a role for supplemental zinc in preventing cognitive and behavioral deficits associated with TBI.     

Chronic intermittent nicotine administration attenuates traumatic brain injury-induced cognitive dysfunction

Traumatic brain injury (TBI) initiates immediate and secondary neuropathological cascades that can result in persistent neurological dysfunction. Previous studies from our laboratory have shown that experimental rat brain injury causes a rapid and persistent decrease in CNS alpha7* nicotinic cholinergic receptor (nAChr) expression. The purpose of this study was to investigate whether intermittent nicotine injections could improve cognitive performance in the Morris water maze (MWM) following experimental brain injury. Adult male rats were anesthetized and subjected to a 1.5 mm controlled cortical impact (CCI) injury of the somatosensory cortex. Animals received twice daily i.p. nicotine injections for 11 days prior to CCI, 11 days following CCI or during both pre- and post-surgical intervals. MWM training was initiated 12 days post-injury. In the training phase of cognitive testing, twice-daily nicotine treatment following injury attenuated trauma-induced deficits in the distance traveled to reach the escape platform. This group of animals also had improvements in several measures of the probe test, including time spent, distance traveled and total entries into the target quadrant. TBI caused significant deficits in alpha7* nAChr expression in several regions of the hippocampus and cerebral cortex, which were largely unaffected by intermittent nicotine treatment. However, nicotine treatment up-regulated [(3)H]-epibatidine binding to non-alpha7* nAChrs, attenuating TBI-induced deficits in receptor expression in several brain regions evaluated. These results suggest that nicotine is efficacious at attenuating CCI-induced cognitive deficits in a manner independent of changes in alpha7* nAChr expression, perhaps via up-regulation of non-alpha7* nAChrs.     

Alterations in neuronal calcium levels are associated with cognitive deficits after traumatic brain injury

Traumatic brain injury (TBI) survivors often suffer from a post-traumatic syndrome with deficits in learning and memory. Calcium (Ca(2+)) has been implicated in the pathophysiology of TBI-induced neuronal death. However, the role of long-term changes in neuronal Ca(2+) function in surviving neurons and the potential impact on TBI-induced cognitive impairments are less understood. Here we evaluated neuronal death and basal free intracellular Ca(2+) ([Ca(2+)](i)) in acutely isolated rat CA3 hippocampal neurons using the Ca(2+) indicator, Fura-2, at seven and thirty days after moderate central fluid percussion injury. In moderate TBI, cognitive deficits as evaluated by the Morris Water Maze (MWM), occur after injury but resolve after several weeks. Using MWM paradigm we compared alterations in [Ca(2+)](i) and cognitive deficits. Moderate TBI did not cause significant hippocampal neuronal death. However, basal [Ca(2+)](i) was significantly elevated when measured seven days post-TBI. At the same time, these animals exhibited significant cognitive impairment (F(2,25)=3.43, p<0.05). When measured 30 days post-TBI, both basal [Ca(2+)](i) and cognitive functions had returned to normal. Pretreatment with MK-801 blocked this elevation in [Ca(2+)](i) and also prevented MWM deficits. These studies provide evidence for a link between elevated [Ca(2+)](i) and altered cognition. Since no significant neuronal death was observed, the alterations in Ca(2+) homeostasis in the traumatized, but surviving neurons may play a role in the pathophysiology of cognitive deficits that manifest in the acute setting after TBI and represent a novel target for therapeutic intervention following TBI.     

Association between a cannabinoid receptor gene (CNR1) polymorphism and cannabinoid-induced alterations of the auditory event-related P300 potential

The biochemical sequelae that follow traumatic brain injury (TBI) are numerous and affect many different brain functions at different points of time as the secondary cascades progress. The complexity of the resulting pathophysiology is such that a singular therapeutic intervention may not provide adequate benefit and a combination of drugs targeting different pathways may be needed. Two of the most widely studied injury mechanisms are oxidative stress and inflammation. Numerous studies have suggested that pharmacological agents targeting either of these pathways may produce an improvement in histological and functional outcome measures. We hypothesized that combining melatonin, a potent antioxidant, with minocycline, a bacteriostatic agent that also inhibit microglia, would provide better neuroprotection than either agent used alone. To test this hypothesis, we subjected anesthetized adult male rats to a 1.5mm controlled cortical impact and administered melatonin or vehicle in the acute post-injury period followed by daily minocycline or vehicle injections beginning the following day in a 2×2 study design. The animals were allowed to recover for 5 days before undergoing Morris water maze (MWM) testing to assess cognitive functioning following injury. There was no significant difference in MWM performance between the vehicle, melatonin, minocycline, or combination treatments. Following sacrifice and histological examination for neuroprotection, we did not observe a significant difference between the groups in the amount of cortical tissue that was spared nor was there a significant difference in [(3)H]-PK11195 binding, a marker for activated microglia. These results suggest that neither drug has therapeutic efficacy, however dosing and/or administration issues may have played a role.     

Chronic methylphenidate treatment enhances water maze performance following traumatic brain injury in rats

Methylphenidate (MPH), a central nervous system stimulant with dopaminergic activity, facilitates neurobehavioral outcome following cortical suction ablation injury, but its potential efficacy following experimental traumatic brain injury (TBI) is unknown. Thus, beginning 24 h after controlled cortical impact injury or sham surgery, male Sprague–Dawley rats were injected (i.p.) once daily for 18 days with either MPH (5 mg/kg) or saline vehicle (VEH) and motor function assessed on post-operative days 1–4, followed by Morris water maze training to find a hidden platform on days 14–18. The MPH treatment regimen was ineffective in accelerating beam-balance or beam-walk recovery, but did significantly decrease swim latencies when compared to VEH-treated controls. The results are consistent with published studies showing improved outcome with MPH therapy. Furthermore, this positive finding with delayed treatment suggests that strategies that enhance catecholamine neurotransmission during the chronic post injury phase may be a useful adjunct in ameliorating some of the neurobehavioral sequelae following TBI in humans.     

Chronic administration of antipsychotics impede behavioral recovery after experimental traumatic brain injury

Antipsychotics are often administered to traumatic brain injured (TBI) patients as a means of controlling agitation, albeit the rehabilitative consequences of this intervention are not well known. Hence, the goal of this study was to evaluate the effects of risperidone (RISP) and haloperidol (HAL) on behavioral outcome after experimental TBI. Anesthetized rats received either a cortical impact or sham injury and then were randomly assigned to five TBI (RISP 0.045mg/kg, RISP 0.45mg/kg, RISP 4.5mg/kg, HAL 0.5mg/kg and VEHicle 1mL/kg) and three Sham (RISP 4.5mg/kg, HAL 0.5mg/kg and VEH 1mL/kg) groups. Treatments began 24h after surgery and were provided once daily for 19 days. Behavior was assessed with established motor (beam-balance/walk) and cognitive (spatial learning/memory in a water maze) tasks on post-operative days 1-5 and 14-19, respectively. RISP and HAL delayed motor recovery, impaired the acquisition of spatial learning, and slowed swim speed relative to VEH in both TBI and sham groups. These data indicate that chronic administration of RISP and HAL impede behavioral recovery after TBI and impair performance in uninjured controls.     

Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat

Recent studies have demonstrated nicotinamide (NAM), a soluble B-group vitamin, to be an effective treatment in experimental models of traumatic brain injury (TBI). However, research on this compound has been limited to administration regimens starting shortly after injury. This study was conducted to establish the window of opportunity for NAM administration following controlled cortical impact (CCI) injury to the frontal cortex. Groups of rats were assigned to NAM (50 mg/kg), saline (1 ml/kg), or sham conditions and received contusion injuries or sham procedures. Injections of NAM or saline were administered at 15 min, 4 h, or 8 h post-injury, followed by five boosters at 24 h intervals. Following the last injection, blood was taken for serum NAM analysis. Animals were tested on a variety of tasks to assess somatosensory performance (bilateral tactile adhesive removal and vibrissae-forelimb placement) and cognitive performance (reference and working memory) in the Morris water maze. The results of the serum NAM analysis showed that NAM levels were significantly elevated in treated animals. Behavioral analysis on the tactile removal test showed that all NAM-treated groups facilitated recovery of function compared with saline treatment. On the vibrissae-forelimb placing test all NAM-treated groups also were significantly different from the saline-treated group. However, the acquisition of reference memory was only significantly improved in the 15-min and 4-h groups. In the working memory task both the 15-min and 4-h groups also improved working memory compared with saline treatment. The window of opportunity for NAM treatment is task-dependent and extends to 8 h for the sensorimotor tests but only extends to 4 h post-injury in the cognitive tests. These results suggest that a 50 mg/kg treatment regimen starting at the clinically relevant time point of 4 h may result in attenuated injury severity in the human TBI population.     

Effects of lisuride hydrogen maleate on pericontusional tissue metabolism, brain edema formation, and contusion volume development after experimental traumatic brain injury in rats

After traumatic brain injury (TBI), the primary insult is followed by a cascade of secondary events which lead to enlargement of the primary lesion and are potentially amenable to therapeutic intervention. Lisuride is a dopaminergic agonist with additional serotoninergic, adrenergic, and glutamate antagonistic properties. In lack of previous data on lisuride in TBI, and based on well documented changes of dopamine metabolism after TBI, we speculated that lisuride could provide neuroprotection in the acute and post-acute stage of controlled cortical impact (CCI) injury in rats. The effect of varying dosages of lisuride on physiological parameter was investigated. Cerebral microdialysis (CMD) was employed to provide a temporal profile of lactate, pyruvate, glucose and glutamate in the pericontusional brain tissue. Additionally, brain edema formation and the development of contusion volume were assessed. In this study, no effect of treatment was seen on physiological parameters or microdialysis profiling of tissue metabolites. Whereas posttraumatic increase in brain water content and an increase in contusion volume could be observed, there was no significant effect of treatment. Taken together, our results suggest that lisuride does not provide neuroprotection in the CCI model at the acute and subacute stages. Based on the available literature, however, it might be possible that dopamine agonists such as lisuride, respectively, improve outcome in terms of cognitive function in a chronic setting.     

Association between cognitive performance and functional outcome following traumatic brain injury: A longitudinal multilevel examination

Objective: Individuals' cognitive abilities predict functional outcomes following traumatic brain injury (TBI). However, it is not known to what extent concurrent cognitive abilities affect the magnitude or the rate of functional recovery. The current study modeled the progression of functional outcome as it related to background, injury severity, and cognitive variables over the first year postinjury. Method: This study comprised 111 individuals with moderate-to-severe TBI assessed on average at 3, 6, and 13 months postinjury. In addition, 79 healthy controls were assessed at a single time point. Each assessment consisted of an administration of a neuropsychological battery-comprising measures of memory, information processing speed, and executive functions-as well as an administration of the Mayo-Portland Adaptability Inventory to examine functional outcomes. Results: Older age, lower levels of education, and greater days of posttraumatic amnesia were associated with poorer functional outcomes. The addition of cognitive variables resulted in better models than simply considering background and injury severity variables. However, the results showed that the model comprising executive functions best characterized the progression of functional outcomes. Conclusions: The findings indicate that consideration of cognitive ability, rather than reliance on demographic and injury severity variables, provide a more accurate representation of functional outcome over the first year postinjury. In addition, the results suggest that specific cognitive domains, particularly executive functions, are likely to have the strongest effect on functional outcomes. (PsycINFO Database Record (c) 2012 APA, all rights reserved).     

The synthetic NCAM-derived peptide, FGL, modulates the transcriptional response to traumatic brain injury

Cerebral responses to traumatic brain injury (TBI) include up- and downregulation of a vast number of proteins involved in endogenous inflammatory responses and defense mechanisms developing postinjury. The present study analyzed the global gene expression profile in response to cryo-induced TBI by means of microarray analysis. Adolescent rats were subjected to TBI and treated with either placebo or a neural cell adhesion molecule (NCAM)-derived fibroblast growth factor receptor (FGFR) agonist, FGL peptide, which has been demonstrated to have neuroprotective effects. mRNA levels were measured at various time-points postlesion (6 h, 1 day and 4 days). The effects of injury, treatment, and injury-treatment interaction were observed. TBI alone rendered a large number of genes affected. Analysis of lesion and treatment interactions resulted in a clear effect of the interaction between injury and FGL-treatment compared to injury and placebo-treatment. Genes affected by TBI alone included inflammation markers, protein kinases, ion channel members and growth factors. Genes encoding regulators of apoptosis, signal transduction and metabolism were altered by the interaction between FGL-treatment and TBI. FGL-treatment in non-injured animals rendered genes regulating signaling, transport and cytoskeleton maintenance significantly increased. Thus, the hypothesis of a putative neuroprotective role of FGL was supported by our findings.     

Establishing a Clinically Relevant Large Animal Model Platform for TBI Therapy Development: Using Cyclosporin A as a Case Study

We have developed the first immature large animal translational treatment trial of a pharmacologic intervention for traumatic brain injury (TBI) in children. The preclinical trial design includes multiple doses of the intervention in two different injury types (focal and diffuse) to bracket the range seen in clinical injury and uses two post‐TBI delays to drug administration. Cyclosporin A (CsA) was used as a case study in our first implementation of the platform because of its success in multiple preclinical adult rodent TBI models and its current use in children for other indications. Tier 1 of the therapy development platform assessed the short‐term treatment efficacy after 24 h of agent administration. Positive responses to treatment were compared with injured controls using an objective effect threshold established prior to the study. Effective CsA doses were identified to study in Tier 2. In the Tier 2 paradigm, agent is administered in a porcine intensive care unit utilizing neurological monitoring and clinically relevant management strategies, and intervention efficacy is defined as improvement in longer term behavioral endpoints above untreated injured animals. In summary, this innovative large animal preclinical study design can be applied to future evaluations of other agents that promote recovery or repair after TBI.