Relationship between circulating IGF-1 levels and traumatic brain injury-induced hippocampal damage and cognitive dysfunction in immature rats

It is well known that traumatic brain injury (TBI) induces the cognitive dysfunction resulting from hippocampal damage. In the present study, we aimed to assess whether the circulating IGF-I levels are associated with cognition and hippocampal damage in 7-day-old rat pups subjected to contusion injury. Hippocampal damage was examined by cresyl violet staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Spatial memory performance was assessed in the Morris water maze. Serum IGF-1 levels decreased in both early and late period of TBI. Decreased levels of serum IGF-1 were correlated with hippocampal neuron loss and spatial memory deficits. Circulating IGF-1 levels may be predictive of cognitive dysfunction resulted from hippocampal damage following traumatic injury in developing brain. Therapy strategies that increase circulating IGF-1 may be highly promising for preventing the unfavorable outcomes of traumatic damage in young children.     

Effect of treadmill exercise on Purkinje cell loss and astrocytic reaction in the cerebellum after traumatic brain injury

The cerebellum is one of the brain areas, which is selectively vulnerable to forebrain traumatic brain injuries (TBI). Physical exercise in animals is known to promote cell survival and functional recovery after brain injuries. However, the detailed pathologic and functional alterations by exercise following an indirect cerebellar injury induced by a TBI are largely unknown. We determined the effects of treadmill exercise on survival of Purkinje neurons and on a population of reactive astrocytes in the gyrus of lobules VIII and IX of the cerebellum after TBI. The rats were divided into four groups: the sham-operation group, the sham-operation with exercise group, the TBI-induction group, and the TBI-induction with exercise group. Cell biological changes of Purkinje neurons following indirect cerebellar injury were analyzed by immunohistochemistry. TBI-induced loss of calbindin-stained Purkinje neurons in the posterior region of the cerebellum and TBI also increased formation of reactive astroyctes in both the granular and molecular layers of the cerebellar posterior region. Treadmill exercise for 10 days after TBI increased the number of calbindin-stained Purkinje neurons and suppressed formation of reactive astroyctes. The present study provides the possibility that treadmill exercise may be an important mediator to enhance survival of Purkinje neurons in TBI-induced indirect cerebellar injury.     

大蒜素抑制脑缺血-再灌注诱导的海马神经元凋亡及其机制初探

目的：探讨大蒜素抗脑缺血-再灌注诱导的海马神经元凋亡作用及其机制。方法： 采用大鼠全脑缺血-再灌注模型，应用流式细胞仪检测海马神经元凋亡率；采用比色法测定海马组织NO和MDA含量及SOD活性。结果： I-R组大鼠海马神经元凋亡率、海马组织NO和MDA含量明显高于sham组，而SOD活性显著低于sham组；静脉给予大蒜素预处理可抑制上述变化，且呈剂量依赖性效应。结论： 大蒜素具有抑制全脑缺血-再灌注诱导的海马神经元凋亡作用及抗氧化作用；大蒜素的抗氧化作用可能是其抑制海马神经元凋亡的重要机制之一。     

Memory and executive functions correlates of self-awareness in traumatic brain injury

Objective: The purpose of this study was to investigate the contribution of executive functions (EF) components and episodic and working memory variables, as well as clinical and demographic factors, to awareness of cognitive ability in traumatic brain injury (TBI).

Methods: Sixty-five TBI patients (mild: n?=?26; moderate/severe: n?=?39) took part in the study. Independent stepwise regression models were calculated for EF and memory predictors, with awareness being measured by patient/informant discrepancy in the Patient Competency Rating Scale.

Results: Models with EF variables indicated that semantic verbal fluency and age are the best predictors of awareness, whereas models including mnemonic functions suggested verbal delayed episodic recall and TBI severity as predictors.

Conclusions: These results are discussed in relation to clinical implications, such as the need to focus efforts of rehabilitation in the cognitive abilities related to awareness, and theoretical models.     

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     

脑外伤小鼠海马水通道蛋白-9表达的变化

目的探讨脑外伤小鼠海马水通道蛋白-9(aquaporin 9,AQP9)表达的变化。方法40只Balb/c小鼠随机分为假手术组(10只)和脑外伤组(30只)。脑外伤组依据脑外伤的不同时间点再分6 h、1 d、3 d三个小组,每组10只。免疫组化和Western blot检测各组小鼠海马AQP9蛋白的表达。RT-PCR方法检测各组小鼠海马AQP9 mRNA的表达变化。结果免疫组化和Western blot结果发现,脑外伤组小鼠海马AQP9蛋白表达量明显高于假手术组(P<0.05);RT-PCR结果也发现,脑外伤组小鼠海马AQP9 mRNA表达量明显高于假手术组(P<0.05)。结论脑外伤小鼠海马AQP9表达明显升高。     

Direct hippocampal injection of pseudo lentivirus-delivered nerve growth factor gene rescues the damaged cognitive function after traumatic brain injury in the rat

Traumatic brain injury (TBI) treatment is a long-term process and requires repeated medicine administration, which, however, can cause high expense, infection, and hemorrhage to patients. To investigate how a long-term expression of nerve growth factor (Ngf) gene affects the injured hippocampus function post-TBI, in this study, a pseudo lentivirus carrying the β-Ngf fusion gene, with green fluorescence protein (GFP) gene, was constructed to show the gene expression and its ability of protecting cells from oxidative damage in vitro. Then, the pseudo lentivirus-carried β-Ngf fusion gene was directly injected into the injured brain to evaluate its influence on the injured hippocampus function post-TBI in vivo. We found that the expression of the pseudo lentivirus-delivered β-Ngf fusion gene lasted more than four-week after the cell transduction and the encoded β-NGF fusion protein could induce the neuron-like PC12 cell differentiation. Moreover, the hippocampal injection of the pseudo lentivirus-carried β-Ngf fusion gene sped the injured cognitive function recovery of the rat subjected to TBI. Together, our findings indicate that the long-term expression of the β-Ngf fusion gene, delivered by the pseudo lentivirus, can promote the neurite outgrowth of the neuron-like cells and protect the cells from the oxidative damage in vitro, and that the direct and single dose hippocampal injection of the pseudo lentivirus-carried β-Ngf fusion gene is able to rescue the hippocampus function after the TBI in the rat.     

Neuroprotective effects of resveratrol against traumatic brain injury in immature rats

Childhood trauma resulting in traumatic brain injury (TBI) due to accidents and abuse is the major cause of death and dysfunction in the young. Since there are no approved specific pharmacological agents that block the progression of the secondary injury, the current management of TBI is mainly supportive. We aimed to determine the effect of resveratrol on hippocampal damage and behavioral deficits in 7-day-old rat pups subjected to contusion injury. Resveratrol was injected intraperitoneally at the doses of 100 mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining and behavioral alterations were evaluated using open field and novel object recognition tests 2 weeks after trauma. Histopathological evaluation showed that treatment with a single dose of 100 mg/kg resveratrol (i.p.) after the trauma significantly ameliorated the trauma induced hippocampal neuron loss at ipsilateral and contralateral hippocampal brain regions of rats. Additionally, treatment with resveratrol decreased anxiety and increased cortex/hippocampus dependent memory of animals subjected to blunt head trauma. These results show that acute treatment of resveratrol has a neuroprotective role against trauma induced hippocampal neuron loss and associated cognitive impairment in rats.     

Possible roles of COX-1 in learning and memory impairment induced by traumatic brain injury in mice

People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI.     

Impaired emotional contagion following severe traumatic brain injury

Empathy deficits are widely-documented in individuals after severe traumatic brain injury (TBI). This study examined the relationship between empathy deficits and psychophysiological responsivity in adults with TBI to determine if impaired responsivity is ameliorated through repeated emotional stimulus presentations. Nineteen TBI participants (13 males; 41 years) and 25 control participants (14 males; 31 years) viewed five repetitions of six 2-min film clip segments containing pleasant, unpleasant, and neutral content. Facial muscle responses (zygomaticus and corrugator), tonic heart rate (HR) and skin conductance level (SCL) were recorded. Mean responses for each viewing period were compared to a pre-experiment 2-min resting baseline period. Self-reported emotional empathy was also assessed. TBI participants demonstrated identical EMG response patterns to controls, i.e. an initial large facial response to both pleasant and unpleasant films, followed by habituation over repetitions for pleasant films, and sustained response to unpleasant films. Additionally, an increase in both arousal and HR deceleration to stimulus repetitions was found, which was larger for TBI participants. Compared to controls, TBI participants self-reported lower emotional empathy, and had lower resting arousal, and these measures were positively correlated. Results are consistent with TBI producing impairments in emotional empathy and responsivity. While some normalisation of physiological arousal appeared with repeated stimulus presentations, this came at the cost of greater attentional effort.     

Exacerbation of apoptosis of cortical neurons following traumatic brain injury in par-4 transgenic mice

Traumatic brain injury (TBI) is a significant clinical problem, yet few effective strategies for treating it have emerged. People that sustain and survive a TBI are left with significant cognitive, behavioral, and communicative disabilities. Apoptotic neuronal death occurs following TBI. Prostate apoptosis response-4 (Par-4) is a death domain-containing protein initially characterized as a critical regulator of apoptosis in prostate cancer cells. We have recently generated and characterized Par-4 transgenic mice in which the expression of the par-4 transgene was limited to cells of neuronal lineage. We now provide evidence that, in cortical neurons from these mice, Par-4 drastically increases apoptotic neuronal death in both in vitro and in vivo models of TBI. In vitro experiments were performed in 7-day-old primary cultures of cortical neurons using a previously published, scratch-induced mechanical trauma model. Neurons that overexpress Par-4 showed not only a significant decrease in overall neuron survival after TBI compared to wild-type cells, but also exhibited a sharper decrease in mitochondrial transmembrane potential, a higher degree of free radical accumulation, and earlier activation of caspase-3 than wild-type cells did. In vivo experiments were performed utilizing a weight drop TBI model. A significantly increased volume of cortical injury and exacerbated activation of caspase-3 were observed in Par-4 transgenic mice when compared to those in wild-type mice. These data suggests that aberrant Par-4 expression exacerbates neuronal cell death following TBI by altering mitochondrial function, enhancing oxidative damage, and execution of apoptosis via caspase activation.     

Effect of APOE polymorphisms on early responses to traumatic brain injury

To investigate the relationship between apolipoprotein E (APOE) polymorphisms and the severity of traumatic brain injury (TBI) in acute stage in the cohort of mainland Chinese patients. We prospectively identified admissions to the two neurosurgical departments for head injury. A total of 110 subjects with TBI (80 males and 30 females, with mean age of 43.87 years) were enrolled from December 2003 to May 2004, and demographic and clinical data were collected. Venous blood was collected from patients with TBI on admission to determine the APOE genotype polymorphisms. The APOE genotyping was performed by means of PCR-RFLP. The deterioration of patients’ condition in acute stage (<7 days after TBI) was judged by either of following criteria: decrease of GCS, increase in hematoma volume or delayed hematoma both detected by repeated CT scanning. χ²-test and logistic regression analyses were done by SPSS. The distributions of APOE genotypes and alleles matched Hardy–Weinberg law. In 110 Chinese patients, 19 subjects presented with deteriorated clinical condition after hospitalization, and seven of 17 patients with APOE ?4 (41.2%) had a deteriorated condition which was significantly different from those without APOE ?4 (12 of 93 patients, 12.9%, P = 0.01). However, neither the presence of ?2 nor of ?3 was significantly different from those absent of it (P > 0.05). Logistic regression analyses showed that APOE ?4 was a risk factor (OR = 4.836, P = 0.011, 95% CI 1.443–16.208) to predispose to clinical deterioration after adjusting for patient age, sex, smoking or not, alcohol-drinking or not, injury severity, injury mechanisms, treatments, and pattern of TBI. This finding suggests that the patients with APOE ?4 predispose to clinical deterioration in acute phase after TBI and APOE polymorphisms play a role in early responses to TBI.     

Performance discrepancies on the California Verbal Learning Test: Second Edition (CVLT-II) after traumatic brain injury.

One hundred fourteen patients with traumatic brain injury (TBI), selected from a 5-year series of consecutive rehabilitation referrals, completed the California Verbal Learning Test -- Second Edition (CVLT-II) within 1 year after injury. Various performance contrasts (i.e., proactive interference, retroactive interference, rapid forgetting, and retrieval problems) were evaluated. Initial analyses revealed higher rates of rapid forgetting in the TBI group as compared to the standardization sample. Follow-up analyses between those patients with and without unusual degrees of rapid forgetting did not reveal any significant differences between these groups on demographic or neurological variables (p>0.10 for all variables). It is concluded that performance discrepancies on the CVLT-II should never be used in isolation to determine the presence or absence of acquired cerebral or memory impairment. However, regardless of the cause, such discrepancies may still be relevant for clinical treatment recommendations.     

Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury

Increases of synaptically released zinc and intracellular accumulation of zinc in hippocampal neurons after traumatic or ischemic brain injury is neurotoxic and chelation of zinc has been shown to reduce neurodegeneration. Although our previous studies showed that zinc chelation in traumatically brain-injured rats correlated with an increase in whole-brain expression of several neuroprotective genes and reduced numbers of apoptotic neurons, the effect on functional outcome has not been determined, and the question of whether this treatment may actually be clinically relevant has not been answered. In the present study, we show that treatment of TBI rats with the zinc chelator calcium EDTA reduces the numbers of injured, Fluoro-Jade-positive neurons in the rat hippocampus 24 h after injury but does not improve neurobehavioral outcome (spatial memory deficits) 2 weeks post-injury. Our data suggest that zinc chelation, despite providing short-term histological neuroprotection, fails to improve long-term functional outcome, perhaps because long-term disruptions in homeostatic levels of zinc adversely influence hippocampus-dependent spatial memory.     

创伤性脑损伤后大鼠外周血CD8的变化

目的:探讨外周血CD8在创伤性脑损伤后的变化特点。方法:改良Feeney's自由落体打击法制备创伤性脑损伤模型;ELISA检测大鼠血清中神经元特异性烯醇化酶(NSE)和CD8的含量,双变量分析两者的相关性;Western blot法检测大鼠血液淋巴细胞FasL蛋白的表达。结果:颅脑外伤后大鼠血清CD8升高滞后于NSE。大鼠伤后1 d血清NSE水平即显著升高,伤后3 d达到峰值,随后逐渐下降;大鼠血清CD8在伤后3 d开始升高,峰值出现在伤后7 d,随后逐渐下降。统计分析显示伤后1 d、3 d、7 d的血清的NSE与伤后3 d、7 d、14 d的血清CD8含量变化呈现正相关。但伤后不同时间大鼠血液淋巴细胞FasL蛋白表达的差异均无统计学显著性。结论:创伤性脑损伤后释放入血的NSE刺激机体免疫应答,引起外周血CD8增多,推测其可能与创伤性脑损伤后继发性损伤的免疫应答有关。     

Sex differences in XIAP cleavage after traumatic brain injury in the rat

Sex influences histological and behavioral outcomes following traumatic brain injury (TBI), but the underlying sex-dependent pathomechanisms regulating outcome measures remain poorly defined. Here, we investigated the TBI-induced regulation of the X-linked inhibitor of apoptosis protein (XIAP) that, in addition to suppressing cell death by inhibition of caspases, is involved in signaling cascades, including immune regulation and cell migration. Since estrogen has been shown to have anti-apoptotic properties, we specifically examined sex differences and the influence of estrogen on XIAP processing after TBI. Sprague–Dawley male (TBI-M), female (TBI-F), ovariectomized female (TBI-OVX) and ovariectomized females supplemented with estrogen (TBI-OVX + EST) were subjected to moderate (1.7–2.2 atm) fluid percussion (FP) injury. Animals were sacrificed 24 h after FP injury; cortical tissue (ipsilateral and contralateral) was dissected and analyzed for XIAP processing by immunoblot analysis (n = 6–7/group) or confocal microscopy (n = 2–3/group). Significant differences in XIAP cleavage products in the ipsilateral cortex were found between groups (p < 0.03). Post hoc analysis showed an increase in XIAP processing in both TBI-F and TBI-OVX + EST compared to TBI-M and TBI-OVX (p < 0.05), indicating that more XIAP is cleaved following injury in intact females and TBI-OVX + EST than in TBI-M and TBI-OVX groups. Co-localization of XIAP within neurons also demonstrated sex-dependent changes. Based on these data, it appears that the processing of XIAP after injury is different between males and females and may be influenced by exogenous estrogen treatment.     

Alpha-2 adrenergic challenge with guanfacine one month after mild traumatic brain injury: Altered working memory and BOLD response

Alterations in working memory (WM) are common after traumatic brain injury (TBI). Frontal catecholaminergic systems, including the alpha-2 adrenergic system, modulate WM function and may be affected in TBI. We hypothesized that administration of an alpha-2 adrenergic agonist might improve WM after mild TBI (MTBI). Thirteen individuals with MTBI 1 month after injury and 14 healthy controls (HC) were challenged with guanfacine and placebo prior to administration of a verbal WM functional MRI task. Guanfacine was associated with improved WM performance in the MTBI but not the HC group. On guanfacine the MTBI group showed increased activation within a WM task-specific region of interest. Findings are consistent with the hypothesis that alterations in WM after MTBI may be improved with the alpha-2 agonist guanfacine.     

Electrophysiological markers of cognitive deficits in traumatic brain injury: A review

Event-related potentials (ERPs) and oscillatory activity from the human electroencephalogram (EEG) provides a rich source of data that helps elucidate specific processing impairments in TBI patients. This review will focus on some of the central and disabling cognitive deficits in TBI and how broadband ERP markers and the spectral content of the EEG can help explain abnormalities in brain function that impact upon processing speed, sustained attention, performance monitoring, inhibitory control and cognitive flexibility. Physiological signals also provide useful outcome markers in cognitive intervention studies in conjunction with behavioural endpoints. Potential rehabilitation approaches utilising electrophysiological markers of recovery are also discussed. Progress has been made in recent years in defining key pathophysiological mechanisms in the context of sensitive laboratory paradigms. However, aberrant physiological signals need to be understood more clearly in future studies in terms of the neuroanatomical impact of injury, particularly in relation to the most common type of damage in TBI, disrupting extended white matter fibres.