Emerging treatments for traumatic brain injury

Background: This review summarizes promising approaches for the treatment of traumatic brain injury (TBI) that are in either preclinical or clinical trials. Objective: The pathophysiology underlying neurological deficits after TBI is described. An overview of select therapies for TBI with neuroprotective and neurorestorative effects is presented. Methods: A literature review of preclinical TBI studies and clinical TBI trials related to neuroprotective and neurorestorative therapeutic approaches is provided. Results/conclusion: Nearly all Phase II/III clinical trials in neuroprotection have failed to show any consistent improvement in outcome for TBI patients. The next decade will witness an increasing number of clinical trials that seek to translate preclinical research discoveries to the clinic. Promising drug- or cell-based therapeutic approaches include erythropoietin and its carbamylated form, statins, bone marrow stromal cells, stem cells singularly or in combination or with biomaterials to reduce brain injury via neuroprotection and promote brain remodeling via angiogenesis, neurogenesis, and synaptogenesis with a final goal to improve functional outcome of TBI patients. In addition, enriched environment and voluntary physical exercise show promise in promoting functional outcome after TBI, and should be evaluated alone or in combination with other treatments as therapeutic approaches for TBI.     

Neuroprotective agents in traumatic brain injury

The role of neuroprotection in traumatic brain injury (TBI) is reviewed. Basic research and experimental investigations have identified many different compounds with potential neuroprotective effect. However, none of the Phase III trials performed in TBI have been successful in convincingly demonstrating efficacy in the overall population. A common misconception is that consequently these agents are ineffective. The negative results as reported in the overall population may in part be caused by specific aspects of the head injury population as well as by aspects of clinical trial design and analysis. The heterogeneity of the TBI population causes specific problems, such as a risk of imbalances between placebo and treated groups but also causes problems when a possible treatment effect is evaluated in relation to the prognostic effect present. Trials of neuroprotective agents should be targeted first of all to a population in which the mechanism at which the agent is directed is likely to be present and secondly to a population in which the chances of demonstrating efficacy are realistic, e.g., to patients with an intermediate prognosis. The possibilities for concomitant or sequential administration of different neuroprotective agents at different times deserve consideration. The potential for neuroprotection in TBI remains high and we should not be discouraged by recent failures obtained up until now. Rather, prior to initiating new trials, careful consideration of experimental evidence is required in order to optimise chances for mechanistic targeting and lessons learned from previous experience need to be taken to heart in the design of future studies.     

Recent advances in neuroprotection for treating traumatic brain injury

The fact that traumatic brain injury is the leading cause of death and disability in the most active population (< 45 years of age) of industrialised countries underscores the need for intensified efforts to define and implement effective neuroprotective strategies. However, despite progressively growing knowledge on the mechanisms involved in the pathobiology of traumatic brain injury and promising preclinical findings, most of the neuroprotection trials have failed to deliver the expected level of beneficial effects. Some of the possible reasons underlying the lack of success of these clinical trials are addressed in this review, which describes some of the most promising and/or controversial ongoing clinical trials from their pathophysiological basis. In addition, new neurobiological findings and their consequence for novel neuroprotective approaches are discussed.     

多肽类化合物在颅脑创伤中的研究进展

颅脑创伤每年在全球造成严重的伤亡,至今研究者们依然没有找到有效的临床治疗药物。肽类物质以其安全、易耐受等优势逐渐成为研究开发的热点。对多肽类化合物在颅脑创伤中的神经保护和抗炎作用进行综述。     

Recent advances in the development of multifactorial therapies for the treatment of traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the industrialised world and remains a major health problem with serious socioeconomic consequences. So far, despite encouraging preclinical results, almost all neuroprotection trials have failed to show any significant efficacy in the treatment of clinical TBI. This may be due, in part, to the fact that most of the therapies investigated have targeted an individual injury factor. It is now recognised that TBI is a very heterogeneous type of injury that varies widely in its aetiology, clinical presentation, severity and pathophysiology. The pathophysiological sequelae of TBI are mediated by an interaction of acute and delayed molecular, biochemical and physiological events that are both complex and multifaceted. Accordingly, a successful TBI treatment may have to simultaneously attenuate many injury factors. Recent efforts in experimental TBI have, therefore, focused on the development of neuropharmacotherapies that target multiple injury factors and thus improve the likelihood of a successful outcome. This review will focus on three such novel compounds that are currently being assessed in clinical trials; progesterone, dexanabinol and dexamethasone, and provide an update on the progress of both magnesium and cyclosporin A.     

Neuroprotective effects of ebselen in traumatic brain injury model: involvement of nitric oxide and p38 mitogen‐activated protein kinase signalling pathway

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Emerging pharmacotherapy for treatment of traumatic brain injury: targeting hypopituitarism and inflammation

Introduction: Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the developed world. In particular, TBI is an important cause of death and disability in young adults with consequences ranging from physical disabilities to long-term cognitive, behavioural, psychological and social defects.

Areas covered: There is a large body of evidence that suggest that TBI conditions may adversely affect pituitary function in both the acute and chronic phases of recovery. Prevalence of hypopituitarism, from total to isolated pituitary deficiency, ranges from 5 to 90%. The time interval between TBI and pituitary function evaluation is one of the major factors responsible for variations in the prevalence of hypopituitarism reported. Diagnosis of hypopituitarism and accurate treatment of pituitary disorders offers the opportunity to improve mortality and outcome in TBI conditions.

Expert opinion: The aim of this paper is to review the history and pathophysiology of TBI and to summarize the best evidence of TBI as a cause of pituitary deficiency. Moreover, in this article we will describe the multiple changes which occur within the hypothalamic–pituitary–thyroid axis in critical illness, giving rise to ‘sick euthyroid syndrome’, focus our attention on thyroid hormones circulating levels from the initial insult to critical illness.     

Diffuse traumatic brain injury and the sensory brain

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脑外伤去骨瓣减压术后并发症临床分析（附87例报告）

目的探讨重型颅脑外伤去骨瓣减压术后并发症发生的原因及防治措施。方法回顾分析2006年。2009年我科87例闭合性颅脑外伤去骨瓣减压术后发生的并发症及其发生率、类型与危险因素。结果术后3个月临床随访结果：GOS5分54例,4分21例,3分7例,2分5例;去大骨瓣术后出现并发症以脑膨出、迟发性颅内出血、硬膜下积液多见。结论去骨瓣减压术可能因为发生并发症而降低效果,各种类型并发症有其典型时间窗口发生,对去骨瓣减压术后并发症积极防治、正确处理能有效降低术后死亡率,改善预后。     

重型颅脑损伤外减压治疗效果观察

目的探讨大骨瓣开颅外减压手术治疗重型颅脑损伤的效果。方法回顾我院2009年1月至2012年8月我院收治的72例重型颅脑损伤患者的临床资料,笔者采用大骨瓣外减压手术方式对72例患者进行减压处理。结果72例患者存活64例,8例因救治不及时术中或术后死亡。存活患者经过1-2年的随访,按GOS评分分级,良好38例,中度残废14例,重度残废9例,3例呈植物人状态。8例死亡的患者中,脑干严重损伤而死亡4例,2例死于严重并发症,2例放弃治疗。结论大骨瓣开颅减压手术治疗重型颅脑损伤效果明显,手术方法及时有效。     

单核细胞移动抑制因子对大鼠创伤性颅脑损伤保护作用研究

目的 研究单核细胞移动抑制因子（MLIF）对大鼠颅脑创伤（TBI）的保护作用,并初步探讨其作用机制。方法 将大鼠随机分为5组,假手术组、模型组、MLIF低、中、高剂量组（0.33、1、3 mg/kg）。采用液压冲击法制备大鼠颅脑创伤模型,颅脑打击后30 min内完成首次尾静脉注射给药,每天给药1次,连续给药7 d。分别于给药后1、3、7 d取脑,检测大鼠脑含水量变化;采用试剂盒法检测血清超氧化物歧化酶（SOD）和丙二醛（MDA）水平;HE染色及尼氏染色观察脑组织病理改变。结果 液压打击致大鼠颅脑创伤24 h后,MLIF低、中、高剂量组大鼠脑含水量均显著低于模型组（P<0.01）,MLIF中剂量组（1 mg/kg）效果最好。与模型组比较,创伤后1、3 d,MLIF（1mg/kg）组大鼠脑含水量显著降低（P<0.01）,该组大鼠血清中SOD含量明显升高（P<0.05）和MDA含量显著降低（P<0.05）。HE染色和尼氏染色结果显示,模型组大鼠脑组织病理损伤明显,呈现明显水肿、细胞固缩等;MLIF（1mg/kg）组大鼠脑组织病理损伤得到改善,水肿程度减轻。结论 MLIF可以抑制脑损伤氧化应激及水肿反应,发挥颅脑损伤保护作用。     

重型颅脑创伤高级救治系统研究

目的：研究建立重型颅脑创伤高级救治系统，方法：详述系统的内容，对其6年的应用效果进行分析。结果：该系统涵盖了早期气管插管，迅速复苏与转运，早期CT扫描，早期手术，急性期ICU环境下脑灌注压处理等重型颅脑损伤救治环节，是高度组织化，较科学合理的区域性颅脑创伤系统，能明显降低重型颅脑损伤的死残率，结论：建立创伤系统对重型颅脑损伤的救治有很重要的临床意义。     

35例老年急性重型颅脑损伤的预后分析

目的对老年人急性重型颅脑损伤的预后作一分析。方法对60岁以上格拉斯哥评分(GCS)<8分的颅脑损伤35例临床资料作回顾性分析。结果手术治疗9例,非手术治疗26例;存活8例,其中良好3例、中残4例、植物生存1例;死亡27例,死亡率77.1%。结论老年重型颅脑损伤具有原发性脑干伤、脑挫裂伤及硬膜外血肿少,而以脑内血肿、硬膜下血肿和多发性颅内血肿多的特点,其死亡率高,合并伤多。GCS及老年性疾病可影响其预后。     

重症颅脑外伤患者的监护及护理

目的探讨重症颅脑外伤患者的监护及护理措施。方法回顾性分析笔者所在医院2008年6月～2011年12月收治的58例重症颅脑外伤患者的临床资料,总结临床监护及护理方法。结果本组58例患者治愈38例,好转17例,死亡3例,死亡率为5.17%;术后仅1例出现肺部感染,无其他并发症。结论重症颅脑外伤患者病情重、变化快、预后差,因此临床严密监测、观察患者病情并进行全面、细致的护理,对提高其临床疗效、降低死亡率具有重要意义。     

急性颅脑损伤患者环池形态变化的临床意义

目的 探讨急性颅脑损伤患者环池形态变化及其临床意义.方法 对78例急性颅脑损伤患者行中脑水平环池形态的CT扫描 ,分析其与疗效和预后的关系.结果 中脑水平环池形态分为四型 :Ⅰ型16例 ,环池无变化 ,死亡1例 ;Ⅱ型20例 ,环池部分变窄 ,死亡3例 ;Ⅲ型22例 ,环池部分闭塞 ,死亡8例 ;Ⅳ型20例 ,环池完全闭塞,死亡14例.结论 了解环池形态变化对颅脑损伤的治疗及预后判断有一定意义.     

Endocannabinoids and traumatic brain injury

Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the 'on-demand' synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI.     

Drug targets for traumatic brain injury from poly(ADP-ribose)polymerase pathway modulation

The deleterious pathophysiological cascade induced after traumatic brain injury (TBI) is initiated by an excitotoxic process triggered by excessive glutamate release. Activation of the glutamatergic N-methyl-D-aspartate receptor, by increasing calcium influx, activates nitric oxide (NO) synthases leading to a toxic production of NO. Moreover, after TBI, free radicals are highly produced and participate to a deleterious oxidative stress. Evidence has showed that the major toxic effect of NO comes from its combination with superoxide anion leading to peroxynitrite formation, a highly reactive and oxidant compound. Indeed, peroxynitrite mediates nitrosative stress and is a potent inducer of cell death through its reaction with lipids, proteins and DNA. Particularly DNA damage, caused by both oxidative and nitrosative stresses, results in activation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme implicated in DNA repair. In response to excessive DNA damage, massive PARP activation leads to energetic depletion and finally to cell death. Since 10 years, accumulating data have showed that inactivation of PARP, either pharmacologically or using PARP null mice, induces neuroprotection in experimental models of TBI. Thus TBI generating NO, oxidative and nitrosative stresses promotes PARP activation contributing in post-traumatic motor, cognitive and histological sequelae. The mechanisms by which PARP inhibitors provide protection might not entirely be related to the preservation of cellular energy stores, but might also include other PARP-mediated mechanisms that needed to be explored in a TBI context. Ten years of experimental research provided rational basis for the development of PARP inhibitors as treatment for TBI.     

重型颅脑损伤患者颅脑磁共振(MRI)和磁共振波谱(MRS)的临床研究

目的 探讨重型颅脑损伤患者早期行颅脑磁共振（MRI）和磁共振波谱（MRS）检查的可行性和安全性.方法 选择该院已安全行伤后早期的MRI和MRS检查的20例重型颅脑损伤患者,分析检查结果.结果 头颅MRI检查对弥漫性轴突损伤检出率明显高于头颅CT检查（P＜0.05）;不同位置的中脑损伤患者,其预后有显著差异（P＜0.05）;半年后预后评分,GOS4～5分患者的NAA/Cr、NAA/Cho、Cho/Cr比值与l～3分患者的差异显著（P＜0.05）;Barthal评分＞60分患者的NAA/Cr、NAA/Cho、Cho/Cr比值与41 ～60分和≤40分患者的差异显著（P＜0.05）.结论 MRI和MRS诊断能够提高重型颅脑损伤病变的检出率,早期进行MRS检查有利于发现MRI显示与临床症状不符的颅脑损伤.     

积雪草酸对颅脑损伤的保护作用及其机制研究

目的 研究积雪草酸对颅脑损伤的保护作用及其机制。方法 采用落重法建立大鼠闭合性颅脑损伤模型和液压冲击颅脑损伤模型,测定大鼠脑组织含水量、血脑屏障通透性、以及观察脑组织病理形态学变化,研究积雪草酸对颅脑损伤的保护作用;用酶联免疫吸附测定(ELISA)和聚合酶链式反应(PCR)检测炎症因子肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)的表达,探讨其作用机制。结果 积雪草酸可显著减少颅脑损伤后脑组织含水量,减轻血脑屏障通透性,改善脑组织细胞形态;并且可以显著抑制颅脑损伤后炎症因子TNF-α、IL-1β、IL-6的表达。结论 积雪草酸具有保护颅脑创伤的作用,其作用机制可能与其抑制炎症作用有关。     

重症颅脑损伤继发脑梗死的危险因素分析

目的 探讨分析重型颅脑损伤继发脑梗死的相关危险因素.方法 对2010年1月～2013年1月本院收治的240例重型颅脑损伤继发脑梗死患者的危险因素进行分析.结果 在重型颅脑损伤患者中,共35例（14.58％）继发脑梗死症状,经危险因素分析后,低格拉斯哥评分（GCS）以及脑挫裂伤、低血压或休克、硬膜下血肿、糖尿病、蛛网膜下腔出血、脑疝等临床表现,是重型颅脑损伤患者继发脑梗死症状的危险因素,不同的临床表现继发性脑梗死的发生率比较,差异有统计学意义（P＜0.05）.结论 重型颅脑损伤患者继发脑梗死症状时,应及时进行诊断与相关治疗,以保证患者的生存质量.