吸入麻醉药促发育期神经元凋亡的分子机制

背景 长期以来,人们一直认为吸入麻醉药的麻醉作用是可逆的,对中枢神经系统不会遗留任何副作用.近年基础研究发现,实验动物尤其是处于发育期动物,暴露于吸入麻醉药后,可出现记忆、认知功能障碍.这种现象的产生可能与吸入麻醉药导致的神经元凋亡增加有关.目的 综述吸入麻醉药诱导发育期大脑神经元凋亡可能的分子机制.内容 吸入麻醉药可能通过影响神经递质及受体、信号转导通路,并可引起氧化应激反应、β-淀粉样蛋白质集聚,从而导致神经细胞凋亡.趋向 对吸入麻醉药神经毒性防治的研究起推动作用.     

瞬时感受器电位香草酸受体1与局部麻醉药物神经毒性

背景 瞬时感受器电位香草酸受体1 (transient receptor potential vanilloid 1,TRPV1)是一种非选择性阳离子通道,主要分布于感觉神经纤维,介导伤害性感受的传入.同时,它能够将外来刺激进行整合影响神经递质的释放以及激活细胞内蛋白酶,从而调节突触传递和细胞功能(如细胞凋亡).局部麻醉药物可以激活TRPV1,且在高浓度时具有神经毒性,表现为病理性疼痛和痛觉过敏,可能与神经细胞的损伤有关.目的 综述TRPV1受体在局部麻醉药物外周神经毒性中的作用机制的研究进展.内容 TRPV1受体的活化能够升高神经纤维局部麻醉药物的浓度而增加其阻断效能,同时增加细胞内钙离子浓度,释放谷氨酸及激活N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR),最终通过钙超载、氧化应激损伤及细胞凋亡途径的活化导致神经元凋亡,介导局部麻醉药物物神经毒性反应.趋向 鉴于TRPV1受体在局部麻醉药物神经毒性的发生机制中所起的作用,靶向调节TRPV1受体的功能是否可以防治局部麻醉药物的神经毒性值得研究.     

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.     

全身麻醉药诱发睡眠紊乱的研究进展

全身麻醉药可干扰机体的昼夜节律,诱发术后睡眠紊乱,但其具体的机制尚未完全阐明。研究表明,全身麻醉药可通过激活γ-氨基丁酸(γ-aminobutyric acid,GABA)能受体、抑制NMDA受体引起昼夜节律紊乱。文章简要阐明全身麻醉药诱发睡眠紊乱的机制,重点阐释时钟基因(circadian locomotor output kaput,Clock)在其中发挥的作用,有助于改善围手术期患者的睡眠问题,以期推进舒适化医疗;通过进一步阐释昼夜节律对全身麻醉药的作用,有助于提高麻醉质量,实现精准麻醉。     

全身麻醉药物分子靶点的研究进展

背景 全身麻醉药物通过增强抑制性神经传递和减弱兴奋性神经传递在中枢神经系统中发挥作用.兴奋性神经递质如谷氨酸和乙酰胆碱(acetylcholine,ACh)引起去极化,而抑制性神经递质如γ-氨基丁酸(γ-aminobutyric acid,GABA)和甘氨酸通过超极化或分流兴奋性电流来降低突触后活性.目的 探讨药物分子靶点在全身麻醉中的作用机制.内容 就全身麻醉药物主要分子靶点作简要介绍.趋向 针对麻醉药物分子靶点对全身麻醉的促进作用所进行的研究可能有助于研发出更有效且更安全的麻醉药.     

钾-氯离子协同转运体2参与痛觉敏化形成的研究进展

背景 痛觉敏化的机制尚未清楚,以往研究集中在神经系统兴奋性增强,近年来抑制性功能下调在痛觉敏化中的作用引起关注.中枢神经系统抑制性受体γ-氨基丁酸A(γ-aminobutyric acid A,GABAA)受体的标志性蛋白之一钾-氯离子协同转运体2(K+-Cl-cotransporter 2,KCC2)在神经元从抑制到兴奋的转变中起了重要作用.KCC2通过影响Cl-的浓度来影响γ-氨基丁酸/甘氨酸所介导的抑制作用,进而影响神经系统兴奋性. 目的 就KCC2在痛觉敏化发生过程中的作用及相关通路进行综述. 内容 多种细胞外信号可以激活小胶质细胞并且引起P2X4Rs的上调;P2X4Rs的激活触发脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)从小胶质细胞的释放;BDNF到神经元的酪氨酸蛋白激酶B受体(tyrosine kinase Breceptor,TrkB)信号通路改变KCC2的功能,导致神经元Cl-外排能力的降低,从而抑制γ-氨基丁酸/甘氨酸所介导的抑制作用. 趋向 研究KCC2参与痛觉敏化形成的机制,为痛觉过敏化的治疗提供新的靶点.     

调节全身麻醉药诱导的发育期神经毒性药物研究进展

目前,婴幼儿、新生儿甚至是胎儿在全身麻醉下行手术或检查已不鲜见。部分全身麻醉药物可通过诱导神经细胞凋亡、突触传递障碍等方式导致远期认知和学习记忆功能缺陷的相关研究已有报道。因此,研究全身麻醉药诱导的发育期神经毒性及其相关干预药物的开发对于保证婴幼儿的健康发育十分重要。文章更新汇总了目前有关调节全身麻醉药物诱导的发育期神经毒性的药物研究进展,这些药物可通过减轻细胞凋亡、突触损伤、海马神经元破坏、降低炎症因子表达、激活保护神经细胞通路等方式缓解全身麻醉药物诱导的神经毒性。     

铁死亡调节机制及其与全身麻醉药神经毒性作用的关系

铁死亡是一种新型调节性细胞死亡途径,主要调节机制有谷氨酸代谢、铁代谢和脂质活性氧（reactive oxygen species,ROS）生成等。全身麻醉药引起发育神经元神经毒性作用的具体机制仍无定论。文章综述铁死亡相关分子机制和信号通路及其与全身麻醉药神经毒性作用的关系,期望为靶向铁死亡预防全身麻醉药神经毒性作用提供...     

异丙酚麻醉对新生小鼠海马c-fos表达和caspase-3激活的影响

全麻药可影响中枢神经的发育,导致婴幼儿或幼龄动物发育期后认知功能下降[1-7].异丙酚在小儿和产科麻醉中的应用日益广泛.研究表明,异丙酚麻醉可影响发育期啮齿类动物中枢神经发育[8],还可引起患儿共济失调、幻觉等神经系统损害[9].在中枢神经发育高峰期,阻断NMDA受体或过度激活γ-氨基丁酸A型( GABAA)受体诱发的神经细胞凋亡可影响长期学习记忆功能[10-11].异丙酚可通过激动GABAA受体,直接或间接阻断NMDA受体发挥麻醉效应[12-13],异丙酚对发育期中枢神经功能的影响是否与神经细胞凋亡有关尚有待研究.本研究拟探讨异丙酚麻醉对新生小鼠海马细胞凋亡相关蛋白c-fos表达和caspase-3激活的影响.     

术后认知功能障碍分子机制与麻醉的潜在联系

背景 术后认知功能障碍(postoperative cognitive dysfunction,POCD)的发病机制多年来倍受关注,其中麻醉因素在POCD相关的多种分子生物学改变中起到了重要作用.目的 将POCD分子机制与麻醉间的潜在关系作一系统综述.内容 近年大量动物实验及体外研究发现,全身麻醉药能引起神经细胞相关蛋白退行性变、调节炎性因子表达、与中枢胆碱能受体相互作用并能在特异条件下产生神经毒性物质,均与POCD相关.趋向 麻醉在POCD中的作用机制尚不明确,需要进一步研究以找到其防治方向.     

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.     

全身麻醉药物对发育大脑小胶质细胞影响的研究进展

近年来，全身麻醉药物对发育大脑的影响成为关注的焦点。全身麻醉药物可造成动物胎儿及幼崽随着生长发育出现短期及长期认知功能障碍，而临床中回顾性研究结果与动物实验结果尚不一致。因此，全身麻醉药物对发育大脑有无影响尚无统一定论。小胶质细胞作为中枢神经系统免疫细胞在发育的不同阶段表现不同形态，执行不同的功能，在神经元损伤修复、神经炎症、神经网络构建等方面发挥重要作用。本文将常用全身麻醉药物包括吸入麻醉药、静脉麻醉药、阿片类药物等对发育大脑小胶质细胞的影响机制做一综述。     

氟马西尼对术后认知功能的影响

术后认知功能障碍的发生可能与围术期某些用药有关.这类药物,尤其是部分麻醉药物可产生遗忘,学习能力、注意力、记忆力、定向力降低等认知功能障碍.苯二氮蔁(benzodiazepine,BDZ)受体拮抗剂氟马西尼不仅可通过影响γ-氨基丁酸(gamma-aminobutyrie acid,GABA)受体促进咪达唑仑、丙泊酚、吸入麻醉药的麻醉后苏醒,还能逆转这些药物所致的认知和精神运动功能的损害,有助于患者术后认知功能的及早恢复.氟马西尼联用5-HT3受体阻断剂恩丹西酮可促进乙酰胆碱的释放,从而推测这种联合用药可拮抗与胆碱能水平减少或功能低下相关的认知功能损害.     

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.     

Volatile anesthetics and synaptic transmission in the central nervous system

Long-lasting changes in the synaptic efficacy of signaling between neurons in the central nervous system are thought to be involved in memory consolidation and recall. Such long-lasting changes were first demonstrated by Bliss et al. in 1973. They found that high frequency stimulation to the hippocampus produced an increase in the amplitude of excitatory postsynaptic potentials, which lasted at least for hours. This phenomenon is known as long-term potentiation (LTP). LTP occurs in many synaptic pathways, and some forms of LTP appear to be triggered by the influx of calcium through NMDA receptors. General anesthetics are thought to affect LTP, since clinically relevant concentrations of volatile anesthetics seem to modify ligand-gated ion channels such as glutamate receptors and GABA(A) receptors. Previous studies have shown that volatile anesthetics such as isoflurane and sevoflurane enhance GABA(A) receptor-mediated inhibition, suggesting that general anesthesia is produced, at least in part, by enhancing neural inhibition mediated by GABA(A) receptors. This review focuses on recent research concerning the effects of volatile anesthetics on synaptic transmission, synaptic plasticity, and clinically important diseases imparing synaptic transmission in the central nervous system.     

Do inhalational anesthetics cause cognitive dysfunction?

Increasing evidence indicates that inhalational anesthetics may cause or increase the risk of developing postoperative cognitive dysfunction (POCD), especially in the elderly population. POCD may exist as a transient or long-term complication of surgery and anesthesia and is associated with reduced quality of life. There remains great discrepancy between clinical studies investigating the prevalence of POCD and inhalational anesthetics as many fail to show an association. However, numerous animal studies have suggested that inhalational anesthetics may alter cognitive function via amyloid β accumulation, modified neurotransmission, synaptic changes and dysregulated calcium homeostasis. Other factors such as neuroinflammation and pro-inflammatory cytokines may also play a role. This paper reviews the role of inhalational anesthetics in the etiology and underlying mechanisms that result in POCD.     

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.     

Brief review: Anesthetic neurotoxicity in the elderly, cognitive dysfunction and Alzheimer’s disease

Purpose

Postoperative cognitive decline in the elderly has emerged as a major health concern. In addition, there is a growing interest in the potential relationship between general anesthetic exposure and the onset and progression of Alzheimer’s disease (AD). The available evidence of a possible association between anesthesia, surgery, and long-term cognitive effects, including AD, deserves consideration. In this review, we summarize the evidence for anesthesia-induced neurotoxicity in the elderly, while highlighting the limitations of existing data, and we put the literature into perspective for the clinician.

Principal findings

A growing body of evidence suggests that general anesthetics may be neurotoxic to both young and aging brains. Much of the evidence originates from in vitro and in vivo studies with cells, rodents, and nonhuman primates. Despite the animal data suggesting a relationship between anesthesia and neurotoxicity in the elderly, a definitive link remains elusive in humans.

Conclusions

The possible relation between anesthetic neurotoxicity, postoperative cognitive dysfunction, and AD remains elusive. It remains unclear whether postoperative cognitive decline in the elderly is related more to perioperative stress and related medical co-morbidities.