N-arachidonoyl--serine is neuroprotective after traumatic brain injury by reducing apoptosis

N-arachidonoyl--serine (AraS) is a brain component structurally related to the endocannabinoid family. We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto-parietal skull and the mechanisms involved. A single injection of AraS following injury led to a significant improvement in functional outcome, and to reduced edema and lesion volume compared with vehicle. Specific antagonists to CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) or large conductance calcium-activated potassium (BK) channels reversed these effects. Specific binding assays did not indicate binding of AraS to the GPR55 cannabinoid receptor. N-arachidonoyl--serine blocked the attenuation in phosphorylated extracellular-signal-regulated kinase 1/2 (ERK) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices. Increased levels of the prosurvival factor Bcl-xL were evident 24 hours after injury in AraS-treated mice, followed by a 30% reduction in caspase-3 activity, measured 3 days after injury. Treatment with a CB2 antagonist, but not with a CB1 antagonist, reversed this effect. Our results suggest that administration of AraS leads to neuroprotection via ERK and Akt phosphorylation and induction of their downstream antiapoptotic pathways. These protective effects are related mostly to indirect signaling via the CB2R and TRPV1 channels but not through CB1 or GPR55 receptors.     

r-huEPO对颅脑创伤患者血清NSE影响的临床研究

目的研究重组人促红细胞生成素（recombinant human erythropoietin,r—huEPO）对颅脑创伤患者血清神经元特异性烯醇化酶（neuron—specific enolase,NSE）表达的影响,评价其神经保护作用。方法纳入住院治疗的颅脑创伤患者32例,随机分配到对照组与治疗组,治疗组于规定时间皮下注射r—huEPO。对照组不予r—huEPO处理,其他治疗两组相同。比较治疗后两组患者GCS评分、颅内压及脑水肿变化情况;两组均在研究时间静脉采血,利用双抗体夹心酶联免疫（ELISA）法分析各组NSE变化。结果从临床征象比较,治疗组患者较对照组恢复较好;两组患者血清NSE均随时间变化表达不同,治疗组血清NSE含量低于对照组,差异有统计学意义（P〈0．05）。结论NSE是较为敏感特异的神经元和神经胶质细胞损伤的指标,利用r—huEPO进行红细胞动员,可通过各种机制抑制颅脑创伤后的继发病理损害及其过度炎症反应,对神经系统损伤具有保护作用。     

Breviscapine reduces neuronal injury caused by traumatic brain injury insult:partly associated with suppression of interleukin-6 expression

Breviscapine,extracted from the herb Erigeron breviscapus,is widely used for the treatment of cardiovascular diseases,cerebral infarct,and stroke,but its mechanism of action remains unclear.This study established a rat model of traumatic brain injury induced by controlled cortical impact,and injected 75 μg breviscapine via the right lateral ventricle.We found that breviscapine significantly improved neurobehavioral dysfunction at 6 and 9 days after injection.Meanwhile,interleukin-6 expression was markedly down-regulated following breviscapine treatment.Our results suggest that breviscapine is effective in promoting neurological behavior after traumatic brain injury and the underlying molecular mechanism may be associated with the suppression of interleukin-6.     

Syringaldehyde exerts neuroprotective effect on cerebral ischemia injury in rats through anti-oxidative and anti-apoptotic properties

There are few studies on the neuroprotective effects of syringaldehyde in a rat model of cerebral ischemia. The study aimed to elucidate the mechanisms underlying the neuroprotective effects of syringaldehyde on ischemic brain cells. Rat models of cerebral ischemia were intraperitoneally administered syringaldehyde. At 6 and 24 hours after syringaldehyde administration, cell damage in the brain of cerebral ischemia rats was obviously reduced, superoxide dismutase activity and nuclear respiratory factor 1 expression in the brain tissue were markedly increased, malondi-adehyde level was obviously decreased, apoptosis-related cysteine peptidase caspase-3 and -9 immunoreactivity was obviously decreased, and neurological function was markedly improved. These ifndings suggest that syringaldehyde exerts neuroprotective effects on cerebral ischemia injury through anti-oxidation and anti-apoptosis.     

r—HuEPO对外伤性脑损伤大鼠凋亡基因表达的影响

目的探讨重组人促红细胞生成素（r—HuEPO）对外伤性脑损伤大鼠凋亡基因表达的影响。方法将48只健康成年雄性SD大鼠随机分成4组：r-HuEPO1000U／kg、3000U／kg、5000U／kg治疗组和生理盐水对照组。采用改良的Feeney氏法制作大鼠自由落体脑创伤模型,r—HuEPO干预。一周后麻醉取脑冻存：免疫组织化学法测定脑组织中NF—κB、C-myc和Fas／Fasl的阳性细胞及凋亡细胞数。结果与对照组相比,各组中NF—KB、Fas和Fasl阳性细胞及凋亡细胞数均有显著减少（P〈0．05）,尤其是5000U／kgr—HuEPO组减少最显著（P〈0．01）。结论r—HuEPO可抑制创伤性脑损伤大鼠NF—KB、Fas／Fasl的促凋亡作用,减轻迟发性神经元损伤,从而起到神经保护的作用。     

The effect of traumatic brain injury on children with learning disability

The psychometric performance of 10 children with a history of learning disability (LD) who subsequently experienced a moderate to severe traumatic brain injury (TBI) was evaluated. Compared to premorbid data, children with LD experienced, after TBI, a statistically significant decline on a measure of psychometric intelligence, whereas their performance on measures of academic achievement remained stable. On specific neuropsychological measures, children with LD and TBI did not differ significantly post-injury from matched controls who also had TBI but no prior history of LD. It is concluded that moderate to severe TBI can cause significant additional cognitive impairment in children with LD, and that periodic modifications in the academic curriculum of these children are often needed after injury. Comparison of premorbid and postmorbid psychometric test data is crucial in this respect.     

右美托咪啶对创伤性脑损伤大鼠模型的神经保护作用实验研究

目的探讨右美托咪啶对创伤性脑损伤组织炎症与细胞凋亡影响。方法建立创伤性脑损伤大鼠模型,设置实验组和对照组,其中实验组予以右美托咪啶6μg/kg腹腔注射干预,对照组予以等量生理盐水腹腔注射,损伤后第3天和第7天,采用ELISA检测损伤组织内肿瘤坏死因子(TNF-α)和白介素-1β(IL-1β)浓度水平,Western-bolt分析损伤组织内凋亡信号关键蛋白caspase-3表达,TUNEL法观察损伤组织细胞凋亡情况。结果右美托咪啶处理可明显降低创伤性脑损伤组织内炎性因子TNF-α和IL-1β浓度(P0.05),减少凋亡信号关键蛋白caspase-3表达(P0.05),显著抑制创伤性脑损伤组织中神经细胞凋亡(P0.05)。结论右美托咪啶处理具有明显神经保护作用,其机制可能与减轻创伤性脑损伤组织炎性反应和抑制神经细胞凋亡有关。     

The potential of neural transplantation for brain repair and regeneration following traumatic brain injury

Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent de-velopment in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury.     

Mild traumatic brain injury

Traumatic brain injury (TBI) is one among the most frequent neurological disorders. Of all TBIs 90% are considered mild with an annual incidence of 100–300/100 000. Intracranial complications of mild traumatic brain injury (MTBI) are infrequent (10%), requiring neurosurgical intervention in a minority of cases (1%), but potentially life threatening (case fatality rate 0.1%). Hence, a true health management problem exists because of the need to exclude the small chance of a life‐threatening complication in a large number of individual patients. The 2002 EFNS guideline used the best evidence approach based on the literature until 2001 to guide initial management with respect to indications for computed tomography (CT), hospital admission, observation and follow‐up of MTBI patients. This updated EFNS guideline for initial management in MTBI proposes a more selective strategy for CT when major [dangerous mechanism, Glasgow Coma Scale (GCS) < 15, 2 points deterioration on the GCS, clinical signs of (basal) skull fracture, vomiting, anticoagulation therapy, post‐traumatic seizure] or minor (age, loss of consciousness, persistent anterograde amnesia, focal deficit, skull contusion, deterioration on the GCS) risk factors are present based on published decision rules with a high level of evidence. In addition, clinical decision rules for CT now exist for children as well. Since 2001, recommendations, although with a lower level of evidence, have been published for clinical observation in hospitals to prevent and treat other potential threats to the patient including behavioural disturbances (amnesia, confusion and agitation) and infection.     

黄体酮对创伤性脑损伤大鼠神经细胞凋亡的影响

目的 观察黄体酮对脑外伤后神经细胞凋亡的影响,探讨其对脑外伤(TBI)继发性脑损伤是否存在保护作用.方法 雄性Wistar 大鼠随机分为无脑损伤的假手术(sham)组、脑损伤(TBI)组、脑损伤后注射黄体酮治疗(P-TBI)组及注射二甲基亚砜(DMSO)溶剂(D-TBI)组,每大组24 只,再分1 d、3 d、5 d 和7 d 四个小组,每小组6 只.采用Freeney 法造成鼠脑挫裂伤模型,在伤后四个不同时相点用TUNEL 染色法分别检测四组大鼠脑组织中神经细胞凋亡情况.结果 创伤性脑损伤后凋亡细胞数量在TBI 第1 d 明显增加,TBI后第7 d 神经细胞凋亡达到高峰.伤后注射黄体酮治疗组神经细胞凋亡指数明显下降(P ＜0.05).结论 大鼠TBI 后周围脑组织神经细胞凋亡在伤后持续增加,注射黄体酮能抑制细胞凋亡,对脑组织有一定保护作用.     

Endoplasmic reticulum stress-induced apoptosis in the penumbra aggravates secondary damage in rats with traumatic brain injur y

Neuronal apoptosis is mediated by intrinsic and extrinsic signaling pathways such as the membrane-mediated, mitochondrial, and endo-plasmic reticulum stress pathways. Few studies have examined the endoplasmic reticulum-mediated apoptosis pathway in the penumbra after traumatic brain injury, and it remains unclear whether endoplasmic reticulum stress can activate the caspase-12-dependent apoptotic pathway in the traumatic penumbra. Here, we established rat models of lfuid percussion-induced traumatic brain injury and found that protein expression of caspase-12, caspase-3 and the endoplasmic reticulum stress marker 78 kDa glucose-regulated protein increased in the traumatic penumbra 6 hours after injury and peaked at 24 hours. Furthermore, numbers of terminal deoxynucleotidyl transferase-mediat-ed dUTP nick end labeling-positive cells in the traumatic penumbra also reached peak levels 24 hours after injury. These ifndings suggest that caspase-12-mediated endoplasmic reticulum-related apoptosis is activated in the traumatic penumbra, and may play an important role in the pathophysiology of secondary brain injury.     

Automated monitoring of early neurobehavioral changes in mice following traumatic brain injury

Traumatic brain injury often causes a variety of behavioral and emotional impairments that can develop into chronic disorders. Therefore, there is a need to shift towards identifying early symptoms that can aid in the prediction of traumatic brain injury outcomes and behavioral endpoints in patients with traumatic brain injury after early interventions. In this study, we used the Smart Cage system, an automated quantitative approach to assess behavior alterations in mice during an early phase of traumatic brain injury in their home cages. Female C57BL/6 adult mice were subjected to moderate controlled cortical impact(CCI) injury. The mice then received a battery of behavioral assessments including neurological score, locomotor activity, sleep/wake states, and anxiety-like behaviors on days 1, 2, and 7 after CCI. Histological analysis was performed on day 7 after the last assessment. Spontaneous activities on days 1 and 2 after injury were significantly decreased in the CCI group. The average percentage of sleep time spent in both dark and light cycles were significantly higher in the CCI group than in the sham group. For anxiety-like behaviors, the time spent in a light compartment and the number of transitions between the dark/light compartments were all significantly reduced in the CCI group than in the sham group. In addition, the mice suffering from CCI exhibited a preference of staying in the dark compartment of a dark/light cage. The CCI mice showed reduced neurological score and histological abnormalities, which are well correlated to the automated behavioral assessments. Our findings demonstrate that the automated Smart Cage system provides sensitive and objective measures for early behavior changes in mice following traumatic brain injury.     

颅脑外伤术后应用异丙酚镇静治疗临床回顾

目的探讨异丙酚用于颅脑外伤患者术后镇静的疗效。方法回顾分析715例颅脑外伤手术患者：对照组289例（1998年～2000年）,术后自然苏醒;治疗组426例（2001年-2005年）,术后给予异丙酚镇静治疗,比较两组颅内压、脑灌注压、术后低血压发生率、术后再出血率和术后6个月GOS等指标。结果两组病例术后6h颅内压存在显著差异（P〈0．05）,脑灌注压无显著差异（P=0．07）,低血压发生率无显著差异（P=0．19）,再出血发生率无显著差异（P=0．46）,两组术后6个月的GOS无显著差异（P=0．28）。结论异丙酚能够安全有效的完成颅脑外伤术后的镇静治疗。     

Naltrexone is neuroprotective against traumatic brain injury in mu opioid receptor knockout mice

AimsNaltrexone is a mu opioid receptor (MOR) antagonist used to treat drug dependence in patients. Previous reports indicated that MOR antagonists reduced neurodegeneration and inflammation after brain injury. The purpose of this study was to evaluate the neuroprotective effect of naltrexone in cell culture and a mouse model of traumatic brain injury (TBI).MethodsThe neuroprotective effect of naltrexone was examined in primary cortical neurons co‐cultured with BV2 microglia. Controlled cortical impact (CCI) was delivered to the left cerebral cortex of adult male MOR wild‐type (WT) and knockout (KO) mice. Naltrexone was given daily for 4 days, starting from day 2 after lesioning. Locomotor activity was evaluated on day 5 after the CCI. Brain tissues were collected for immunostaining, Western, and qPCR analysis.ResultsGlutamate reduced MAP2 immunoreactivity (‐ir), while increased IBA1‐ir in neuron/BV2 co‐culture; both responses were antagonized by naltrexone. TBI significantly reduced locomotor activity and increased the expression of IBA1, iNOS, and CD4 in the lesioned cortex. Naltrexone significantly and equally antagonized the motor deficits and expression of IBA1 and iNOS in WT and KO mice. TBI‐mediated CD4 protein production was attenuated by naltrexone in WT mice, but not in KO mice.ConclusionNaltrexone reduced TBI‐mediated neurodegeneration and inflammation in MOR WT and KO mice. The protective effect of naltrexone involves non‐MOR and MOR mechanisms.     

重型颅脑损伤256例临床分析

目的 探讨重型颅脑损伤治疗方法,提高重型颅脑损伤的治愈率和降低致残率、死亡率。方法 对我院2000-01～2005-12收治的256例重型颅脑损伤（GCS≤8分）的患者救治效果进行回顾性分析。结果 256例患者中,174例患者GCS评分6～8分,82例特重型颅脑损伤（GCS评3～5分）,恢复良好148例（57．8％）,中残57例（22．3％）,重残以及植物状态13例（5．1％）,死亡38例（14．9％）。结论 重型颅脑损伤应加强院前急救处理．早期明确诊断,手术中应充分减压以减轻对脑干的压迫,早期行气管切开、亚低温治疗和使用钙离子拮抗剂,昏迷时间较长者行高压氧治疗,密切监测生命体征和颅内压变化,积极防治并发症,是提高治俞率、改善预后和降低致残率、死亡率的有效措施.     

Neuroprotective effects of vagus nerve stimulation on traumatic brain injury

Previous studies have shown that vagus nerve stimulation can improve the prognosis of traumatic brain injury. The aim of this study was to elucidate the mechanism of the neuroprotective effects of vagus nerve stimulation in rabbits with brain explosive injury. Rabbits with brain explosive injury received continuous stimulation(10 V, 5 Hz, 5 ms, 20 minutes) of the right cervical vagus nerve. Tumor necrosis factor-α, interleukin-1β and interleukin-10 concentrations were detected in serum and brain tissues, and water content in brain tissues was measured. Results showed that vagus nerve stimulation could reduce the degree of brain edema, decrease tumor necrosis factor-α and interleukin-1β concentrations, and increase interleukin-10 concentration after brain explosive injury in rabbits. These data suggest that vagus nerve stimulation may exert neuroprotective effects against explosive injury via regulating the expression of tumor necrosis factor-α, interleukin-1β and interleukin-10 in the serum and brain tissue.     

Vascular endothelial growth factor increases neurogenesis after traumatic brain injury

Activation of endogenous stem cells has been proposed as a novel form of therapy in a variety of neurologic disorders including traumatic brain injury (TBI). Vascular endothelial growth factor (VEGF) is expressed in the brain after TBI and serves as a potent activator of angiogenesis and neurogenesis. In this study, we infused exogenous VEGF into the lateral ventricles of mice for 7 days after TBI using mini-osmotic pumps to evaluate the effects on recovery and functional outcome. The results of our study show that VEGF significantly increases the number of proliferating cells in the subventricular zone and in the perilesion cortex. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia and only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF compared with vehicle-treated animals after TBI. Injury size was significantly smaller at 90 days after TBI in VEGF-treated animals, suggesting additional neuroprotective effects of VEGF. In conclusion, VEGF significantly augments neurogenesis and angiogenesis and reduces lesion volumes after TBI. These changes are associated with significant improvement in recovery rates and functional outcome.     

Endogenous adult neurogenesis and cognitive function recovery following traumatic brain injury in the rat hippocampus

BACKGROUND:Endogenous neural progenitor cells play a beneficial role for cognitive recovery following traumatic brain injury.However,there are few classification-control studies aimed at varying graded brain trauma.OBJECTIVE:To observe the effects of adult endogenous neurogenesis on cognitive function repair and regeneration of neural progenitor cells following varying graded traumatic hippocampal injury to determine the significance of endogenous neurogenesis in the repair of brain injury.DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Key Laboratory of Injuries,Variations and Regeneration of Nervous System,Tianjin Medical University General Hospital,from February to October 2009.MATERIALS:Mouse anti-rat 5-bromodeoxyuridine (BrdU) and neuronal nuclei (NeuN) monoclonal antibodies were purchased from Millipore Corporation,USA.METHODS:A total of 45 Wistar rats were randomly assigned to three groups.Mild and severe injury groups were respectively subjected to (182 ± 2) kPa and (284 ± 4) kPa lateral fluid percussion to establish models of brain injury,and the control group was subjected to surgery with no lateral fluid percussion.MAIN OUTCOME MEASURES:Cognitive function was estimated using the Morris water maze.Proliferation,survival,and differentiation of newly generated cells in the injured hippocampus were observed through the use of immunofluorescent staining.RESULTS:At 7 days post-injury,the number of BrdU+ cells in the hippocampal dentate gyrus significantly increased in the mild and severe injury groups compared with the control group (P<0.01).At 61 days post-injury,the number of BrdU7NeuN+ cells in the hippocampal dentate gyrus was significantly greater in the mild injury group compared with the severe injury and control groups (P< 0.01).In addition,the control group exhibited the greatest proportion of surviving cells that differentiated into mature neurons compared with the injury groups (P< 0.01).Moreover,at 61 days post-injury,cognitive function in rats with mild injury recovered to normal levels,whereas the severe injury group exhibited cognitive deficits (P< 0.01).CONCLUSION:Traumatic brain injury may be a stimulation factor for proliferation of neural progenitor cells in the adult hippocampus but severe brain trauma does not lead to an increased number of newly generated cells.Endogenous adult neurogenesis repairs neurological functions to an extent.However,recovery of neurological function remains limited following severe traumatic brain injury.     

Neuritin provides neuroprotection against experimental traumatic brain injury in rats

Objectives: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Neuritin is a neurotrophic factor that regulates neural growth and development. However, the role of neuritin in alleviating TBI has not been investigated.

Methods: In this study, Sprague Dawley rats (n = 144) weighing 300 ± 50 g were categorized into control, sham, TBI and TBI + neuritin groups. The neurological scores and the ultrastructure of cortical neurons, apoptotic cells and caspase-3 were measured by using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Western blot analysis and real-time RT-PCR at various time points post-TBI.

Conclusions: Our findings indicated that neuritin plays a protective role in TBI by improving neurological scores, repairing injured neurons and protecting the cortical neurons against apoptosis through inhibition of caspase-3 expression. Further investigation of the molecular mechanisms underlying caspase-3 inhibition by neuritin will provide a research avenue for potential TBI therapeutics.