全身麻醉药对发育大脑的神经毒性研究进展

背景 每年越来越多的婴幼儿在全身麻醉下接受各种影像学检查和外科手术及重症监护治疗,反复暴露于全身麻醉药物之下.目前,全身麻醉药物是否具有神经毒性这一问题引起了人们的广泛关注. 目的 综述全身麻醉药对发育期大脑产生神经毒性的可能机制及相关研究的最新进展. 内容 就全身麻醉药对发育期大脑产生神经毒性的作用机制、在不同动物实验模型的研究结果、相关临床研究进展及动物实验与临床研究的相关性及局限性等方面内容进行综述. 趋向 目前动物实验及临床研究均不能完全排除全身麻醉药的神经毒性作用,在对全身麻醉药影响神经系统发育的机制深入研究的同时,在儿科手术麻醉时应做到在全面发挥麻醉药治疗作用的同时尽可能降低神经毒性的副作用.     

吸入麻醉药的神经毒性作用及其产生机制

背景 吸入麻醉药具有安全、有效的特点,已广泛应用于各种手术的临床麻醉.大量实验研究表明,常用的吸入麻醉药均有不同程度的神经毒性作用,尤其是对于发育高峰期的大脑. 目的 探讨吸入麻醉药对幼年动物及小儿的神经毒性作用及其可能机制. 内容 吸入麻醉药具有神经毒性,可能会引起幼年动物学习及记忆功能的损伤,影响小儿神经发育导致认知行为障碍.目前认为其机制可能是多途径的,包括受体的影响、突触可塑性变化、脑的炎性反应和相关脑内物质的改变等. 趋向 正确了解吸入麻醉药的神经毒性作用不仅对婴幼儿麻醉药物的选择具有非常重要的指导意义,并且通过探索机制寻找可能的处理方法,为今后的临床处理提供新的思路.     

麻醉药物对星形胶质细胞及其标志蛋白GFAP的影响

星形胶质细胞(astrocyte，AS)在中枢神经系统(central nervous system，CNS)大量存在，其重要功能已经逐渐受到重视。纤维胶质酸性蛋白(glial fibrillary acidic protein，GFAP)是AS的特异性标志蛋白。麻醉药物作用于机体会影响星形胶质细胞的形态和功能。现从AS的形态、分类和功能，GFAP的特性，麻醉药物对AS及GFAP的表达的影响的特点、机制等方面作一综述。     

全身麻醉药对发育大脑神经细胞的影响

<正>目前全球每年有数百万的儿童接受全身麻醉。近些年,麻醉学的研究重点正在向全麻药是否对发育大脑产生神经毒性这一方向转移。麻醉药对发育早期神经功能造成损伤的机制包括神经细胞凋亡和神经发育(包括神经元产生、突触形成、胶质细胞发育)受损等。目前,国内外的研究绝大多数都局限于全麻药对未成熟神经元或突触结构的作用,对其他发病机制缺乏深入地了解。本文将探讨临床常用的全麻药对发育大脑的影响机制,为术后神经学的研究提供新的方向。     

麻醉药物对星形胶质细胞及其标志蛋白GFAP的影响

星形胶质细胞 (astrocyte,AS)在中枢神经系统 (centralnervoussystem ,CNS)大量存在 ,其重要功能已经逐渐受到重视。纤维胶质酸性蛋白 (glialfibrillaryacidicprotein ,GFAP)是AS的特异性标志蛋白。麻醉药物作用于机体会影响星形胶质细胞的形态和功能。现从AS的形态、分类和功能 ,GFAP的特性 ,麻醉药物对AS及GFAP的表达的影响的特点、机制等方面作一综述。     

全身麻醉药物对脑电信号影响的研究进展

脑电信号是脑神经细胞在大脑皮层或头皮表面的总体反映,随着脑电信号监测技术的应用和发展,麻醉过程中进行脑电信号监测可以提示麻醉药物的作用情况,因此麻醉药物对脑电信号的影响是麻醉监测的一个重要研究主题。全身麻醉药物包括静脉麻醉药物和吸入麻醉药物,这些麻醉药物通过可逆性地抑制中枢神经系统,对大脑状态产生影响,最终产生不同程度的镇静作用。在麻醉药物的使用过程中,大脑会呈现出慢频率和大振幅的特点,但不同药物的频谱却各有差异。本文根据现有文献,对不同麻醉药物作用下脑电信号的影响进行综述,为今后的基础和临床研究提供理论基础和新的思路。     

全身麻醉药物导致发育大脑神经凋亡的可能机制

近年来临床及基础研究均提示,全身麻醉药物对于发育期大脑会产生短暂或长期的影响,称为麻醉诱导的神经发育毒性(AIDN)[1]。临床研究难以监测中枢神经系统的损害,只能通过神经心理学测试等手段间接获得神经系统损害的证据。最初的基础研究结果显示妊娠大鼠接受亚浓度的氟烷会影响新生大鼠大脑神经突触的发生[2]。后来有报道：给出生7d后的大鼠注射氯胺酮,会引起广泛的脑神经细胞凋亡,并可能与成年后神经发育紊乱相关[3]。到目前为止,几乎所有的麻醉与镇静药物对于啮齿类动物、灵长类动物的幼崽均可引起广泛的神经细胞凋亡[4],如静脉麻醉药丙泊酚[57]、氯胺酮[8],吸入麻醉药尤其是异氟醚[9],均可引起发育期大脑的神经凋亡及成年后的认知功能损伤,且具有年龄、接触时间、剂量依赖和多种药物协同性[1012]。全身麻醉药物导致发育期中枢神经细胞凋亡的作用机制尚不明确,现将其可能机制综述如下。     

全身麻醉药引发的内质网应激和线粒体功能障碍对阿尔茨海默病影响的研究

背景 阿尔茨海默病(Alzheimer's disease,AD)是一种常见的神经退行性病变,以大脑特定区域蛋白蓄积以及神经元缺失为特点.有研究证实全身麻醉药物可引发内质网应激(endoplasmic reticulum stress,ERS)和线粒体功能障碍,进而引起细胞凋亡,而AD的发病及进展与ERS和线粒体功能障碍密切相关. 目的 探究全身麻醉药引发的ERS和线粒体功能障碍对AD的影响. 内容 介绍ERS及其与线粒体功能障碍之间的联系以及全身麻醉药对AD发病及病程影响. 趋向 ERS、线粒体功能障碍及ERS-线粒体之间的联系近年来成为AD临床治疗的重要靶点,也为全身麻醉药物合理选择及配伍提供新思路.     

意识与脑功能连接性:麻醉药物作用机制的研究进展

背景 功能连接性(整合),相对于解剖结构连接性,是指在耦联的神经系统中信号之间存在统计学上的依赖关系,近年来发现大脑不同区域之间的功能连接性与意识关系密切,而麻醉药物诱导意识丧失的机制很可能与功能连接性有关.目的 现从意识与大脑功能连接性角度对麻醉药物作用机制的研究进展作一综述.内容 静息态功能磁共振(resting state functional magnetic resonance imaging,rs-fMRI)在分析大脑功能连接性方面具有优势,多项研究应用rs-fMRI技术分析全身麻醉药物对脑区功能连接性的影响,提示麻醉药物的可能作用靶点为脑区功能连接性. 趋向 rs-fMRI技术的不断发展,为研究麻醉药物作用机制开辟了新的方向.     

全身麻醉药发育神经毒性的机制及其防治研究进展

背景 越来越多的动物研究显示全身麻醉药能够导致发育神经元的凋亡,流行病学研究亦表明,患儿在3岁前接受长时间或/和多次全身麻醉发生术后认知功能障碍的风险明显增加;然而,全身麻醉药导致发育神经元毒性的机制尚未阐明,临床上也缺乏有效的防治措施.目的 通过综述全身麻醉药导致发育神经元毒性的可能机制,探讨可能的防治措施.内容全身麻醉药通过不同的分子途经调控发育神经元并能够启动或加速神经元的凋亡.首先,由于发育神经元内Cl-的浓度较高,全身麻醉药激活γ-氨基丁酸A(γ-aminobutyric acid A,GABAA)受体后可促进Cl-由胞内流向胞外,进而导致神经元兴奋性中毒.其次,氯胺酮上调能够渗透钙离子的N-甲基-D天冬氨酸(N-methyl-D-aspanate,NMDA)受体可能会导致钙超载.第三,全身麻醉药抑制前体脑源性神经营养因子(brain derived neurotrophic factor,BDNF)向成熟BDNF(mBDNF)的转化,进而通过P75神经营养因子受体(p75 neurotrophin receptor,p75NTR)通路诱导神经元凋亡.第四,一些全身麻醉药也能够造成活性氧自由基(reactive oxygen species,ROS)的积聚,在钙超载和ROS的共同作用下可导致线粒体功能障碍.全身麻醉药物引起神经网络活动的紊乱也可以导致神经元凋亡和认知功能障碍.越来越多的研究发现靶向相关的离子通道、控制钙超载、减少ROS产物以及减轻神经元凋亡可有效保护全身麻醉药物导致的神经元变性.趋向 全身麻醉药可通过不同的分子途经导致发育神经元凋亡,将这些分子或分子途经作为潜在的靶标可以对全身麻醉药诱发的功能障碍进行防治.     

全麻药物对脑神经毒作用的研究进展

从细胞培养、啮齿类动物和非人类灵长类动物的实验研究中得到越来越多的证据:临床常用全麻药物对各期脑神经细胞产生毒性作用,损伤中枢神经系统,特别对处于发育高峰期的大脑影响更大,并影响以后的学习记忆功能.现综述这些事实及目前全麻药物神经毒性作用的机制假设,目的 是让人们对全麻药物毒性作用的最新研究进展有一了解,转变临床麻醉的一些观念.     

General anesthetic-induced neurotoxicity: an emerging problem for the young and old?

PURPOSE OF REVIEW: A growing body of evidence from cells, rodents, and sub-human primates suggests that general anesthetics can be neurotoxic to the developing and senescent brain. We review this evidence and put the studies into perspective for the practicing clinician. RECENT FINDINGS: Studies indicate that a variety of general anesthetics, which act primarily as gamma-amino-butyric acid receptor modulators and N-methyl-D-aspartic acid glutamate receptor antagonists, produce apoptotic neurodegeneration in the developing rodent and nonhuman primate brain. Vulnerability to this neurotoxicity is greatest during the period of synaptogenesis and presumably reflects disruption of the normal balance between excitation and inhibition during a critical period of brain development. Moreover, in the rodent, the neurodegeneration is associated with cognitive impairment into adulthood. Recent data also reveal that general anesthesia produces enduring cognitive impairment in aged but not young rodents and that halothane and isoflurane increase the generation and toxicity of amyloid beta, a protein strongly implicated in the pathogenesis of Alzheimer's disease. The meaning of these experimental results for human surgical patients is unclear, however, because human studies are lacking. SUMMARY: General anesthetics produce neurotoxicity and enduring cognitive impairment in young and aged animals but it is premature to change clinical practice because the issue has not been adequately studied in humans.     

Anesthesia and the developing brain: a way forward for clinical research

It is now well established that many general anesthetics have a variety of effects on the developing brain in animal models. In contrast, human cohort studies show mixed evidence for any association between neurobehavioural outcome and anesthesia exposure in early childhood. In spite of large volumes of research, it remains very unclear if the animal studies have any clinical relevance; or indeed how, or if, clinical practice needs to be altered. Answering these questions is of great importance given the huge numbers of young children exposed to general anesthetics. A recent meeting in Genoa brought together researchers and clinicians to map a path forward for future clinical studies. This paper describes these discussions and conclusions. It was agreed that there is a need for large, detailed, prospective, observational studies, and for carefully designed trials. It may be impossible to design or conduct a single study to completely exclude the possibility that anesthetics can, under certain circumstances, produce long‐term neurobehavioural changes in humans; however , observational studies will improve our understanding of which children are at greatest risk, and may also suggest potential underlying etiologies, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome.     

全身麻醉药对脑发育的影响

随着麻醉领域的不断发展,新生儿麻醉的死亡率明显下降.一系列的研究表明,在脑发育高峰期,药物性阻断N-甲基-D-天(门)冬氨酸受体或过度激动γ-氨基丁酸A型受体会诱发神经细胞凋亡.鉴于全麻药在中枢神经系统的作用机制,麻醉药物对脑发育的影响成为人们研究的热点,其机制的阐明可能对新生儿麻醉用药的合理选用及新药的开发具有指导意义.     

Anesthetic mechanisms revealed by functional brain imaging

Recent advancement in functional brain imaging techniques has revealed much of the global effects of general anesthetics on the human brain. General anesthetics preferentially suppress specific brain areas including the parietal association cortex and the thalamus, part of which appears to mirror the default mode network. Low-level sensory areas are relatively preserved and remain activated even under deep sedation by anesthetics. Functional connectivity analysis by resting-state functional magnetic resonance imaging has shown that general anesthetics moderately suppress functional connectivity of the default mode network. Midazolam-induced loss of consciousness is associated with remarkable suppression of cortico-cortical propagation of evoked currents. Overall, those results prompt us to hypothesize that general anesthetics induce loss of consciousness by disrupting the integrative properties of the cerebral cortex.     

Strategies and experimental models for evaluating anesthetics: effects on the developing nervous system

Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of procedures requiring anesthesia. It has been reported that anesthetic drugs cause widespread and dose-dependent apoptosis in the developing rat brain. The similarity of the physiology, pharmacology, metabolism, and reproductive systems of the nonhuman primate to that of the human, especially during pregnancy, make the monkey an exceptionally good animal model for assessing potential neurotoxic effects of anesthetics. The window of vulnerability to these neuronal effects of pediatric anesthetics is restricted to the period of rapid synaptogenesis, also known as the brain growth spurt period. To minimize the risks to children resulting from the use of anesthesia, the following questions should be addressed: 1. What is the relationship between exposure and brain cell loss for drugs commonly used in the practice of pediatric anesthesia (inhaled anesthetics, midazolam, ketamine, and nitrous oxide)? 2. Are there "class effects," or does each drug need to be considered independently? 3. Are there important interactions among the drugs used as anesthetics contributing to the risk of brain cell death? 4. What is the likely period of human vulnerability? Pharmacogenomic/system biology approaches have great potential for helping to advance the understanding of brain-related biological processes, including neuronal plasticity and neurotoxicity. Because of the complexity and temporal features of how developmental neurotoxicity is manifested, pharmacogenomic/systems biology approaches may prove to be useful tools for enhancing our understanding of the biological processes induced by anesthetics. Therefore, the main purpose of this review is to describe the application of these approaches and models, as well as protection strategies, especially as regards the issue of anesthetic-induced neuronal cell death during development. Much of the discussion that follows is based on experiments conducted with ketamine. This is due in part to the use of ketamine in the early studies and the volume of preclinical experimental work performed with this drug, as well as its use in anesthetic studies in developing rodents and nonhuman primates. Although ketamine use in pediatric anesthesia is relatively limited, the findings of the studies are sufficiently strong to merit concern about the N-methyl-d-aspartate antagonist drugs as a class. Our focus on ketamine should not be construed as implying that the risk of neurodegeneration with ketamine is greater, or less, than with other anesthetics. We are simply describing the effects where we have the most preclinical data.     

睡眠觉醒环路与全身麻醉机制研究进展

背景 全身麻醉与睡眠都表现为觉醒水平的降低,以及对外界环境刺激反应的抑制,二者具有相似的脑电图和局部脑功能变化.近年研究表明,全身麻醉药通过抑制脑内促觉醒神经核团和戚激活促睡眠神经核团发挥镇静催眠及意识消失作用.目的 从睡眠觉醒环路的角度综述全身麻醉神经机制的研究进展.内容 麻醉药诱导的意识消失与自然睡眠觉醒产生的机制并非完全相同,每种麻醉药物作用的靶神经核团也存在一定的差异.趋向 深入研究睡眠觉醒环路及全身麻醉神经机制,将有助于研发新型安全有效的麻醉剂.     

Developmental anesthetic neurotoxicity: from animals to humans?

Several animal studies have demonstrated that most routinely used general anesthetics induce widespread neuroapoptosis and long-term neurocognitive impairment in the immature brain. These findings have generated great interest among pediatric anesthesiologists and other practitioners regarding the safe use of general anesthetics in pediatric patients. Several human retrospective studies failed to confirm whether or not anesthesia exposure during the crucial phase of brain development induces long-term neurocognitive deficits in humans. Since the clinical relevance of the results of general anesthesia in animal experiments is unknown, it is unreasonable to directly utilize the results derived from animals and retrospective human surveys to guide clinical practice at the present time. Clearly, additional prospective randomized controlled trials are needed in humans to determine the effects of general anesthesia on neurodevelopment. In this review, we summarize currently available laboratory and clinical evidence for anesthetic neurotoxicity. Furthermore, we discuss the implications of these results for clinical anesthesia.