Toll样受体4在小胶质细胞炎症反应中的作用与认知功能的关系

概述 小胶质细胞在术后早期中枢炎症反应中担当主角.而Toll样受体4(toll-like receptor 4,TLR4)在小胶质细胞的活化与炎症反应中发挥着不可或缺的作用.中枢炎症细胞因子可通过多种途径影响中枢有关受体或递质功能,从而影响学习记忆和认知能力. 目的 探讨TLR4在小胶质细胞炎症反应中作用及与认知功能的关系. 内容 主要从4个方面进行综述:TLR4与小胶质细胞的关系、小胶质细胞与中枢炎症的关系、炎症和TLR4对认知的影响. 趋向 小胶质细胞在中枢神经系统(central nervous system,CNS)的炎症反应中担当主角.TLR4在小胶质细胞的激活中起关键作用,但TLR4在小胶质细胞相关的中枢炎症反应和认知中的作用尚不清楚.     

小胶质细胞在病理性Tau蛋白所致认知功能损害中的作用

Tau蛋白过度磷酸化形成的神经元纤维缠结(neurofibrillary tangle,NFT)被认为是引起认知功能损害的重要原因之一。过度磷酸化Tau蛋白以多种形式存在于中枢神经系统,对神经元产生毒性作用,并激活小胶质细胞产生免疫应答反应。文章探讨了病理性Tau蛋白中枢神经毒性作用,分析了小胶质细胞与病理性Tau蛋白相互作用在认知功能损害中所扮演的角色,阐述了通过诱导小胶质细胞分化方向调控分化后小胶质细胞分泌因子,干预病理性Tau蛋白所致的认知功能损害。     

小胶质细胞与疼痛敏化调控

小胶质细胞激活后充当中枢神经系统的免疫效应细胞,活化的小胶质细胞是脑内细胞因子的重要来源和作用部位,参与疼痛敏感化的病理发生过程。研究证实,神经损伤后小胶质细胞是中枢神经系统中反应较早的胶质细胞,激活的小胶质细胞释放的一些生物活性物质,能导致星形胶质细胞的激活,反过来维持较持久的疼痛状态。本文就脊髓小胶质细胞在神经病理性疼痛中的变化及其分子机制和临床联系作一综述。     

JAK2/STAT3信号通路在大脑缺血缺氧后小胶质细胞活化中的作用

缺血缺氧脑病（Hypoxic-ischemic encephalopathy,HIE）是导致新生儿死亡和婴幼儿神经发育障碍的主要原因,部分患儿有不同程度的神经系统后遗症,如脑瘫、认知和运动功能发育障碍。缺血缺氧可激活JAK2/STAT3信号通路,进而导致小胶质细胞异常活化,引发神经炎症反应;通过下调JAK2/STAT3信号通路可抑制小胶质细胞异常活化,改善神经系统炎性损伤。当前缺血缺氧脑病的治疗方法有限,因此研究小胶质细胞活化的调控机制对于缺血缺氧脑病的治疗具有重要临床价值。本文对JAK2/STAT3信号通路在小胶质细胞活化中的作用及二者相互关系的研究进展作一综述,以期为缺血缺氧脑病的治疗提供新的研究思路。     

衰老大脑小胶质细胞异常激活与中枢性炎症研究进展

背景 中枢性炎症反应在老年术后认知功能障碍(post operative cognitive dysfunction,POCD)、阿尔茨海默病(Alzheimer's disease,AD)、帕金森病(Parkinson's disease,PD)等慢性神经退行性疾病的发生发展中至关重要,其具体机制尚不明确.目的 阐明衰老大脑小胶质细胞活性改变及其异常激活对中枢炎症反应的加剧作用.内容 对衰老大脑小胶质细胞异常激活及其可能机制进行阐述.趋向 如何抑制衰老大脑小胶质细胞免疫通路的异常激活是今后的研究方向.     

小胶质细胞参与调控术后认知功能障碍的研究进展

背景 术后认知功能障碍（postoperative cognitive dysfunction, POCD）在老年患者中发生率较高。小胶质细胞是一种中枢神经细胞,在中枢神经系统（central nervous system, CNS）生理和病理过程中均发挥重要作用。越来越多的研究表明,小胶质细胞广泛参与神经退行性疾病的发生与发展。 目的 探讨小胶质细胞在POCD中的作用。 内容 简述小胶质细胞对学习记忆的调控作用及其与POCD的相关性。 趋向 小胶质细胞在POCD中的具体作用尚未阐明,继续对此进行深入探究可能为预防和治疗POCD提供新的思路。     

髓样细胞激发受体-2在中枢神经系统疾病中的研究进展

背景 髓样细胞激发受体(triggering receptor expressed by myeloid cells,TREM)是一种免疫球蛋白超家族受体,TREM-2在中枢神经系统(central nervous system,CNS)主要表达于小胶质细胞.研究发现TREM-2的激活可产生抑制小胶质细胞过度活化、减少促炎症因子分泌进而减轻CNS炎症损伤程度的作用.因此,TREM-2的激活可能产生神经保护作用.目的 探讨TREM-2在CNS疾病中的研究进展,通过减轻CNS炎症,进而为治疗CNS疾病提供新的治疗策略.内容 介绍TREM家族的特性,阐述TREM-2在不同CNS疾病中的功能,探讨其发挥作用的相关机制.趋向 TREM-2可能成为减轻CNS炎症反应的新靶点,为CNS疾病的治疗提供新的方向.     

交质细胞在慢性疼痛中的病理及保护作用

目前认为,胶质细胞在病理性疼痛和慢性疼痛的发病机制中起了重要作用。胶质细胞受到激活后,星形胶质细胞和小胶质细胞都会做出反应,释放许多的信号分子。这些信号分子,或者具有保护作用,或者具有病理效应。在此,简单综述了胶质细胞对病理性疼痛的病理机制和其对神经元保护作用的基础。胶质细胞抗炎作用的保护性机制,已被作为研究新型神经病理性疼痛药物的靶点。考虑到目前慢性疼痛的普遍性和目前药物疗效的有限性。在新的关于胶质细胞——神经元细胞相互关系的理论指导下．研究和制定新的疼痛控制策略是值得的。     

术后认知功能障碍与中枢炎症

术后认知功能障碍（postoperative cognmve dysfunction,POCD）好发予老年患者,虽已渐为熟知。但POCD的发病机制仍不清楚。中枢炎症反应可能是其发病机制之一．涉及神经退行性变．手术应激、细胞因子释放、GSK-3β和胶质细胞的活性等多因素。     

脊髓神经元和胶质细胞激活在三种神经病理性疼痛大鼠模型脊髓水平致痛机制中的作用

目的比较脊髓神经元和胶质细胞(星形胶质细胞和小胶质细胞)激活在三种大鼠神经病理性疼痛模型脊髓水平致痛机制中的作用。方法 SD 大鼠24只,体重150g～200g,随机分为4 组,每组6只,分别为对照组、CCI 组、SNL 组和 SNI 组。对照组不实施手术；CCI、SNL、SNI 组分别于左侧制作慢性坐骨神经缩窄损伤模型(CCI)、脊神经结扎模型(SNL)和保留性脊神经损伤模型(SNI)。术前3d 至术后15d 隔日使用机械刺激测定术侧后爪50%缩爪阈值。术后15d 测痛后,用多聚甲醛灌注大鼠,取L_(5,6)脊髓,进行免疫组化实验；用抗原癌基因蛋白 c-Fos、星形胶质细胞标记蛋白(GFAP)和小胶质细胞标记蛋白(OX-42)抗体分别检测神经元、星形胶质细胞和小胶质细胞的激活状况。结果术后7d CCI、SNL、SNI 组术侧50%缩爪阈值均达到最低值,并维持至术后15d；术后15d,对照组、CCI 组、SNL 组和 SNI 组50%缩爪阈值分别为14.1±1.5、2.6±0.5、1.5±0.6、(0.8±0.4)g,大小顺序依次为对照组、CCI 组、SNL 组、SNI 组(P＜0.05)。与对照组比较,CCI、SNL 和 SNI 组Ⅳ～Ⅵ层 c-Fos 阳性神经元数量增加,脊髓背角Ⅰ或Ⅱ层星形胶质细胞及Ⅰ～Ⅳ层小胶质细胞的激活状态升高(P＜0.05), 但 CCI、SNL 和 SNI 组间脊髓背有Ⅳ～Ⅵ层 c-Fos 阳性神经元数量、术侧脊髓背角Ⅰ或Ⅱ层星形胶质细胞的及Ⅰ～Ⅳ层小胶质细胞激活状态差异无统计学意义(P＞0.05)。结论三种神经病理性疼痛大鼠模型中脊髓背角神经元、星形胶质细胞和小胶质细胞的激活状况一致,提示其在脊髓水平致痛机制相似。     

老年人中枢炎症反应与认知功能障碍的相关性研究进展

背景 认知功能障碍好发于老年人群,与手术、感染、创伤以及麻醉等多个危险因素相关,其中术后认知功能障碍(postoperative cognitive dysfunction,POCD)一直受到很多学者的关注.然而有关认知功能障碍确切的病因和机制仍不清楚,临床上也缺乏有效的预防和治疗策略.许多研究发现中枢炎症反应可能是认知功能障碍重要的病理生理机制之一. 内容 回顾老年人中枢炎症反应的发生、神经炎症反应对认知功能的损害以及抗炎策略在认知损害防治方面的研究进展. 目的 为认知功能障碍尤其是POCD病理生理机制的进一步研究奠定良好的基础. 趋向 在认知功能障碍防治方面具有一定的指导意义并为其提供新的思路.     

Chronic pain and neuroinflammation

In rheumatology, chronic pain most often sets in after a musculoskeletal injury. Its persistence is not always due to the progression of the initial injury, but in some cases to the onset of central sensitization. Much scientific data suggests that this central sensitization is caused by multiple complex interactions between the nervous system and immune system. Afferent nerve fibers carrying pain information are responsible for peripheral sensitization partly linked to inflammation molecules. These afferent fibers release neurotransmitters in the dorsal root ganglion and dorsal horn of the spinal cord, capable of activating microglia, which are the local immune cells. The activated microglia will produce pro-inflammatory cytokines, chemokines and neuropeptides capable of interacting with the second-order neuron, but also segmental and descending inhibitory neurons. This is referred to as neuroinflammation, which will amplify the hypersensitivity of second-order neurons, otherwise called central sensitization. This neuroinflammation will be able to reach the higher brain structures, which are involved in pain modulation and the emotional and cognitive aspects of pain. The aim of this update is to describe the pathophysiology of chronic pain, incorporating the latest scientific data on neuroplasticity and neuroinflammation.     

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。     

Cyclin D1 gene ablation confers neuroprotection in traumatic brain injury

Cell cycle activation (CCA) is one of the principal secondary injury mechanisms following brain trauma, and it leads to neuronal cell death, microglial activation, and neurological dysfunction. Cyclin D1 (CD1) is a key modulator of CCA and is upregulated in neurons and microglia following traumatic brain injury (TBI). In this study we subjected CD1-wild-type (CD1(+/+)) and knockout (CD1(-/-)) mice to controlled cortical impact (CCI) injury to evaluate the role of CD1 in post-traumatic neurodegeneration and neuroinflammation. As early as 24?h post-injury, CD1(+/+) mice showed markers of CCA in the injured hemisphere, including increased CD1, E2F1, and proliferating cell nuclear antigen (PCNA), as well as increased Fluoro-Jade B staining, indicating neuronal degeneration. Progressive neuronal loss in the hippocampus was observed through 21 days post-injury in these mice, which correlated with a decline in cognitive function. Microglial activation in the injured hemisphere peaked at 7 days post-injury, with sustained increases at 21 days. In contrast, CD1(-/-) mice showed reduced CCA and neurodegeneration at 24?h, as well as improved cognitive function, attenuated hippocampal neuronal cell loss, decreased lesion volume, and cortical microglial activation at 21 days post-injury. These findings indicate that CD1-dependent CCA plays a significant role in the neuroinflammation, progressive neurodegeneration, and related neurological dysfunction resulting from TBI. Our results further substantiate the proposed role of CCA in post-traumatic secondary injury, and suggest that inhibition of CD1 may be a key therapeutic target for TBI.     

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.     

神经炎症对术后认知功能障碍影响的研究进展

术后认知功能障碍（POCD）是手术和麻醉后的常见并发症,老年患者预后较差。POCD表现为注意力、意识、知觉和判断力下降,并时常伴随情绪和人格行为的异常改变,对患者和其家庭有较大的社会和经济影响。POCD相关机制包括中枢神经炎症和外周炎性因子的共同作用,其中神经炎症在POCD的病理生理发展过程中十分重要,然而神经炎症参与POCD发生与发展的机制尚不明确。本文章就神经炎症及其相关研究机制与POCD的关系做一综述,以期为探究POCD的发病机制和寻找新的潜在靶点提供新思路。     

神经炎症反应在术后认知功能障碍中作用的研究进展

背景 在老年患者的心脏手术和非心脏手术中,术后认知功能障碍(postoperative cognitive dysfunction,POCD)已经成为一种常见的并发症.POCD导致患者并发症增加,医疗消耗增加,患者病死率升高.近年来大量研究发现POCD各种发病机制都通过一个共同通路即神经炎症. 目的 进一步研究神经炎症反应对POCD发生、发展的作用机制和防治措施.内容 以神经炎症反应为中心,围绕神经炎症、炎症因子、抗炎和炎症抑制反应对POCD的影响进行综述. 趋向 预防性抗炎治疗防止POCD的发生、发展.     

Serum creatinine patterns in coronary bypass surgery patients with and without postoperative cognitive dysfunction

Renal dysfunction is common after coronary artery bypass graft (CABG) surgery. We have previously shown that CABG procedures complicated by stroke have a threefold greater peak serum creatinine level relative to uncomplicated surgery. However, postoperative creatinine patterns for procedures complicated by cognitive dysfunction are unknown. Therefore, we tested the hypothesis that postoperative cognitive dysfunction is associated with acute perioperative renal injury after CABG surgery. Data were prospectively gathered for 282 elective CABG surgery patients. Psychometric tests were performed at baseline and 6 wk after surgery. Cognitive dysfunction was defined both as a dichotomous variable (cognitive deficit [CD]) and as a continuous variable (cognitive index). Forty percent of patients had CD at 6 wk. However, the association between peak percentage change in postoperative creatinine and CD (parameter estimate = -0.41; P = 0.91) or cognitive index (parameter estimate = -1.29; P = 0.46) was not significant. These data indicate that postcardiac surgery cognitive dysfunction, unlike stroke, is not associated with major increases in postoperative renal dysfunction. IMPLICATIONS: We previously noted that patients with postcardiac surgery stroke also have greater acute renal injury than unaffected patients. However, in the same setting, we found no difference in renal injury between patients with and without cognitive dysfunction. Factors responsible for subtle postoperative cognitive dysfunction do not appear to be associated with clinically important renal effects.