Oligodendrocyte vulnerability following traumatic brain injury in rats

Experimental and clinical findings demonstrate that traumatic brain injury (TBI) results in injury to both gray and white matter structures. The purpose of this study was to document patterns of oligodendrocyte vulnerability to TBI. Sprague Dawley rats underwent sham operated procedures or moderate fluid percussion brain injury. Quantitative immunohistochemical analysis was performed on animals perfusion-fixed at 3 (n=9) or 7 (n=9) days post-surgery. Within the ipsilateral external capsule and corpus callosum, numbers of APC-CC1 immunoreactive oligodendrocytes were significantly decreased at 3 or 7 days post-TBI compared to sham rats (p<0.03). At both posttraumatic survival periods, double-labeling studies indicated that oligodendrocytes showed increased Caspase 3 activation compared to sham. These data demonstrate regional patterns of oligodendrocyte vulnerability after TBI and that oligodendrocyte cell loss may be due to Caspase 3-mediated cell death mechanisms. Further studies are needed to test therapeutic interventions that prevent trauma-induced oligodendrocyte cell death, subsequent demyelination and circuit dysfunction.     

自噬在创伤性脑损伤中的作用

自噬(autophagy)是真核细胞在营养与能量缺乏情况下,通过分解亚细胞成分提供生物合成原料,使蛋白质和细胞器得以循环利用的一种降解代谢途径,同时调控线粒体更新及过氧化物酶体等,从而维持细胞稳态.     

脑创伤对大鼠学习记忆功能的影响

目的：观察ＴＢＩ后大鼠主动性条件回避反应（ＡＣＡＲ———穿梭箱实验，ｓｈｕｔｌｅｂｏｘｔｅｓｔ）及被动性条件回避反应（ＰＣＡＲ———步入与步下实验，ｓｔｅｐｔｈｒｏｕｇｈａｎｄｓｔｅｐｄｏｗｎｔｅｓｔ）的变化。方法：用２０ｇ重物从不同高度垂直坠落至大鼠一侧暴露的硬脑膜复制脑创伤（ＴＢＩ）模型。结果：重度ＴＢＩ后大鼠ＡＣＡＲ的习得率和保持率均出现下降，ＰＣＡＲ的步入和步下潜伏期缩短；轻度ＴＢＩ后仅表现出ＡＣＡＲ的习得率降低。结论：ＴＢＩ易导致脑高级功能障碍，其受损程度与原发伤情有关。     

壳聚糖包载人脐带间充质干细胞对创伤性脑损伤大鼠的治疗作用及机制

目的 探讨壳聚糖包载人脐带间充质干细胞(hUC-MSCs)对创伤性脑损伤大鼠的治疗效果及相关机制.方法 构建40只创伤性脑损伤SD大鼠模型,根据干预方案的不同,分为对照组(n=10)和壳聚糖组(n=10)、干细胞组(n=10)和联合治疗组(n=10),采用mNSS量表评价大鼠运动功能,Morris水迷宫法评价学习记忆能...     

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     

Delayed glucose treatment improves cognitive function following fluid-percussion injury

Experimental traumatic brain injury (TBI) results in marked neurochemical and metabolic changes. Research has demonstrated that after the initial insult the brain undergoes an immediate state of hypermetabolism followed by a sustained period of hypometabolism. The altered extra- and intracellular environment can compromise neuronal performance and limit functional recovery. If brain metabolism is depressed chronically after TBI, then interventions that are designed to increase metabolism may be beneficial to outcome. Glucose treatment has been shown to improve cognition in many populations, particularly those with cognitive deficits. The following experiments examined the effects of delayed postinjury glucose supplementation on cognitive function following TBI. Male Sprague-Dawley rats received either sham or lateral fluid-percussion (LFP) injury. Cognitive functioning was assessed with the Morris water maze (MWM) on postinjury days 11-15. In the first experiment, saline or 100mg/kg glucose was administered 10 min before cognition assessment. Injured animals treated with glucose displayed significantly shorter latencies to reach the goal platform compared to injured saline-treated animals. Glucose had no effect on sham-injured rats. In the second experiment, injured rats were given daily injections of saline or 100mg/kg glucose for 10 days beginning 24h after injury. Rats were then tested in the MWM on days 11-15 without glucose or saline treatment. In this experiment, glucose treatment did not affect MWM performance. These data provide evidence that the chronic energy supplementation after TBI improves outcome when administered shortly before cognitive assessment.     

Oral methylphenidate establishes a conditioned place preference in rats

Emerging data suggest that illicit methylphenidate abuse is a growing problem. Although abuse of the drug typically occurs by the intranasal route, oral (per os; p.o.) methylphenidate also has abuse potential. The present study compared the effects of p.o. and intraperitoneal (i.p.) methylphenidate in rats using the conditioned place preference (CPP) procedure. Young adult male Sprague-Dawley rats were trained to consume oyster crackers injected initially with saline. Next, rats were randomly assigned to receive p.o. or i.p. methylphenidate (3 or 10mg/kg) or saline immediately or 30min prior to 30min conditioning trials. Methylphenidate or saline were each paired 4 times with an end compartment; preference for the methylphenidate-paired compartment was then assessed on a drug-free session. When given immediately prior to conditioning, significant CPP was obtained with both 3 and 10mg/kg of i.p. methylphenidate, but only with 10mg/kg of p.o. methylphenidate. When given 30min prior to conditioning, there was no evidence of CPP for any dose of i.p. or p.o. methylphenidate. These findings are the first demonstration that p.o. methylphenidate has rewarding effects, although i.p. methylphenidate is obtained at a 3mg/kg dose which did not establish CPP with p.o. administration. The lack of CPP following 30min pretreatment also suggests that conditioning may require the CS to be associated with a US of ascending, rather than descending, brain levels of methylphenidate. These results are consistent with clinical evidence of the reduced abuse liability of p.o. methylphenidate relative to methylphenidate taken by other (e.g., intranasal) routes.     

Experimental treatment for focal hyperglycemic ischemic brain injury in the rat

Hyperglycemia aggravates ischemic brain injury, possibly due to the activation of signaling pathways involving reactive oxygen species, Src and mitogen-activated protein kinases. The aim of this study was to investigate the effects of the spin trap agent α-phenyl-N-tert-butyl nitrone (PBN), the Src family kinase inhibitor PP2 and the MEK1-inhibitor U0126 on focal hyperglycemic ischemic brain injury. Temporary middle cerebral artery occlusion (90 min) was induced in four groups of rats (PBN, PP2, and U0126 vs. control). Neurological testing and tetrazolium red staining were performed after 1 day. PBN decreased the infarct volume by 70% compared with the control (P<0.05) and a tendency towards reduced infarcts was seen in the PP2 or U0126 groups. Furthermore, neurological testing was consistent with the volumetric analysis. In conclusion, PBN appears to be a potential neuroprotective agent in hyperglycemic, focal ischemic brain injury, while the efficacy of PP2 and U0126 could not be confirmed by the present data. This study was approved by the Uppsala Ethical Committee of Animal Research (C133/2).     

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.     

The effects of selenium against cerebral ischemia-reperfusion injury in rats

It is known that the brain tissue is extremely sensitive to ischemia-reperfusion (IR) injury and therefore, brain ischemia and consecutive reperfusion result in neural damage and apoptosis. The proinflammatory cytokines such as tumor necrosis factor alfa (TNF-α) and interleukin-1 beta (IL-1β) are produced during neurological disorders including cerebral ischemia. On the other hand, nerve growth factor (NGF), which is essential for the differentiation, survival and functions of neuronal cells in the central nervous system, regulate neuronal development through cell survival and cell death signaling. In the present study, we aimed to investigate the effect of selenium (Se) on prefrontal cortex and hippocampal damage in rats subjected to cerebral IR injury. Selenium was injected intraperitoneally at the doses of 0.625 mg/(kg day) after induction of IR injury. Prefrontal cortex and hippocampal damage was examined by cresyl-violet staining. Apostain and caspase-3 immune staining were used to detect apoptosis. TNF-α, IL-1β and NGF levels were also evaluated. Histopathological evaluation showed that treatment with selenium after ischemia significantly attenuated IR-induced neuronal death in prefrontal cortex and hippocampal CA1 regions of rats. Apoptotic cells stained with apostain and caspase-3 were significantly decreased in treatment group when compared with the IR group. Additionally, treatment with selenium decreased the TNF-α and IL-1β levels and increased the NGF levels in prefrontal cortex and hippocampal tissue of animals subjected to IR. The present results suggest that selenium is potentially a beneficial agent in treating IR-induced brain injury in rats.     

Sleep disturbances following mild traumatic brain injury in childhood

OBJECTIVE: To examine objective and subjective reports of sleep disturbance in school-aged children who had sustained mild traumatic brain injury (TBI) at least 6 months prior to the study. METHODS: Eighteen children aged 7-12 years with a history of mild TBI (GCS 13-15. LOC < 15 min) were compared to 30 children with orthopedic injuries using actigraphy and parental and self-report sleep questionnaires. RESULTS: Parents reported greater sleep disturbance in the mild TBI group. No significant differences were found in parental ratings of daytime sleepiness, child-reported sleep difficulties, or objective (actigraph) sleep measures. CONCLUSIONS: The finding of greater parental reports of sleep disturbance following mild TBI 6 months after injury requires greater exploration and future research with a larger sample followed from the point of injury would seem appropriate.     

血压对大鼠脑缺血/再灌注损伤的影响

目的： 研究血压变化对大鼠脑缺血/再灌注模型的影响。方法: 44只SD大鼠随机分为低血压组、正常血压组、高血压组及尿激酶/高血压组,制作缺血2 h再灌注24 h脑缺血/再灌注损伤模型,再灌注起始分别应用降压药物或升压药物改变平均动脉压水平（约20 mmHg）持续1 h,观察其神经功能改善、梗死体积、出血性转化的发生。结果: 再灌注24 h,低血压组神经功能恶化,其它各组均有不同程度的恢复;随着血压的升高,大鼠脑梗死体积有逐渐减小的趋势;尿激酶/高血压组出血性转化发生率最高,其次为低血压组及高血压组,而正常血压组最低;尿激酶/高血压组梗死灶周围皮层区MMP-9阳性细胞计数与其它各组比较均有显著差异（P<0.05）。结论: 再灌注期间升高血压有利于脑缺血大鼠神经功能预后的改善。大鼠脑缺血再灌注模型出血性转化发生率随着血压的升高或降低均有增加的趋势,其发生可能与MMP-9的过量表达有关。     

Histone deactylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury

Traumatic brain injury (TBI) induces a number of pathological events ranging from neuronal degeneration and tissue loss to impaired neuronal plasticity and neurochemical dysregulation. In rodents, exposure of brain-injured animals to environmental enrichment has been shown to be an effective means of enhancing learning and memory post-injury. Recently, it has been discovered that environmental enrichment may enhance neuronal plasticity through epigenetic changes that involve enhanced histone acetylation, a property that can be mimicked by the use of histone deactylase (HDAC) inhibitors. We therefore evaluated the consequences of the HDAC inhibitor sodium butyrate on the learning and memory of brain-injured mice. In contrast to a previous report using a mouse neurodegeneration model, sodium butyrate (1.2 g/kg daily for four weeks) did not improve learning and memory when tested after the completion of the drug treatment paradigm. In addition, sodium butyrate administration during the reported period of neurodegeneration (days 0–5) also offered no benefit. However, when administered concurrently with training in the Morris water maze task (beginning on day 14 post-injury), sodium butyrate improved learning and memory in brain-injured mice. Interestingly, when these mice were subsequently tested in an associative fear conditioning task, an improvement was observed. Taken together, our findings indicate that HDAC inhibition may mimic some of the cognitive improvements seen following enriched environment exposure, and that the improvement is observed when the treatment is carried out current with behavioral testing.     

大鼠创伤性脑损伤后海马齿状回中脑脂结合蛋白的表达变化

Objective To investigate the change of brain lipid binding protein(BLBP) expression in hippocampus dentate gyrus(DG) at different time points after traumatic brain injury (TBI). Methods Seventy-two rats were divided into the injured group, sham group and control group randomly, and then were subjected to a lateral fluid percussion injury (FPI). Western blotting was used to detect BLBP expression. Brains were sectioned for immunofluorescence staining of BLBP and Vimentin at the time points of 1, 3, 7, 14 days after TBI.Results The results of Western blotting showed that the BLBP expression was lower than that of control group at 1 day post injury（EM>P/EM><0.01） and reached the peak compared with the other groups at 7 days after injury（EM>P/EM><0.01）, then descended at 14 days compared with control group after injury（EM>P/EM><0.01）. The changes of BLBP and Vimentin double-label positive cells were consistent with the results of Western blotting. The BLBP and Vimentin double-label positive cells were found mainly at the subgranular zone of ipsilateral injured hippocampus DG, and most of them were radial glia like cells; BLBP and Vimentin double-labelled positive cells were found at the hilus of DG at 7days after injury, and most of them looked like reactive astrocytes. Conclusion The expression of BLBP in DG after TBI decreased firstly, then increased and reached peak at 7 days after injury, decreased dramatically again at last. The     

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.     

Cooling of the brain through oxygen flushing of the nasal cavities in intubated rats: an alternative model for treatment of brain injury

Local cooling of the brain by respiration has been found in several animal species with a rete mirabile in the carotid artery/cavernous sinus complex. The present experiment was made to investigate whether a similar cooling could be found in the rat, which does not have a rete. Eleven rats were anesthetized and intubated. Three thermoprobes were inserted into the brain (two probes) and rectum, and the temperatures measured continuously. The nasal cavities were flushed with oxygen (250-1000 ml/min) during 15-min periods, interrupted by 15-min control periods. The mean brain temperature decreased by 0.43 +/- 0.03 degree C (n = 86, P < 0.005) with individual values up to 1.11 degrees C during the flushing periods. The decrease was oxygen-flow dependent, but not correlated to the rectal temperature. It is concluded that even an animal species without a rete mirabile is able to decrease the brain temperature through nasal cooling. The cooling was probably connected to the blood flow. If the results can be extrapolated to man (no rete mirabile), brain temperature can be decreased by nasal flushing with air or oxygen in intubated patients with hyperthermia. We also suggest that this simple treatment will reduce the infarct volume after head injury, trauma, or brain ischemia.     

赛庚啶对大鼠脑损伤脑皮质和脑微血管中5—HT含量的影响

采用高效液相色谱－电化学检测器检测大鼠（１８０只）脑损伤后脑皮质及脑微血管中５－ＨＴ含量变化，并选用５－ＨＴ受体阻断剂赛庚啶治疗，观察其对脑损伤后脑皮质及脑微血管５－ＨＴ水平变化的影响。结果表明：脑损伤后５－ＨＴ水平显著升高，神经细胞和脑微血管内皮病理变化与５－ＨＴ代谢改变有密切关系，赛庚啶可显著降低脑皮质及脑微血管中５－ＨＴ含量，并减轻脑继发性损害。     

颅脑外伤后局部脑组织中P物质和生长抑素的表达及意义

本文旨在分子水平探讨人脑外伤后神经肽的变化,为脑外伤后病理生理变化机制提供理论依据。采用免疫组织化学技术和多功能真彩色病理图像分析系统(CMIAS)对31例脑外伤患者局部脑损伤区和12例无脑损伤猝死患者相同脑区神经细胞中P物质(SP),生长抑素(SS)的表达进行了检测。结果得出脑伤患者局部伤区及周围神经细胞中SP、SS表达较尸检对照组明显减少并具时程特点。但与伤情及预后无显著关系。本实验表明SP、SS在颅脑损伤的病理生理过程中起了重要作用。     

Sleep and wake disturbances following traumatic brain injury

Traumatic brain injury (TBI) is a major health concern in industrialised countries. Sleep and wake disturbances are among the most persistent and disabling sequelae after TBI. Yet, despite the widespread complaints of post-TBI sleep and wake disturbances, studies on their etiology, pathophysiology, and treatments remain inconclusive. This narrative review aims to summarise the current state of knowledge regarding the nature of sleep and wake disturbances following TBI, both subjective and objective, spanning all levels of severity and phases post-injury. A second goal is to outline the various causes of post-TBI sleep-wake disturbances. Globally, although sleep-wake complaints are reported in all studies and across all levels of severity, consensus regarding the objective nature of these disturbances is not unanimous and varies widely across studies. In order to optimise recovery in TBI survivors, further studies are required to shed light on the complexity and heterogeneity of post-TBI sleep and wake disturbances, and to fully grasp the best timing and approach for intervention.     

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.