脑缺血后星形胶质细胞能量代谢的改变:研究进展及临床意义

背景 星形胶质细胞是脑内重要的胶质细胞,对神经元的能量代谢、信号转导、电活动等方面都有重要的支持作用.脑缺血后星形胶质细胞能量代谢的变化,影响了神经元的存活和整个大脑的功能恢复. 目的 以星形胶质细胞能量代谢改变为切入点,探索治疗脑缺血疾病的新策略. 内容 从星形胶质细胞正常的能量代谢、缺血后星形胶质细胞能量代谢的改变、缺血引起能量代谢改变的可能机制以及临床意义4个方面进行综述. 趋向 为寻找基于星形胶质细胞的缺血早期干预和治疗措施提供新思路.     

肉桂鞣质B-1对脊髓星形胶质细胞增殖的调节作用及对血清氧葡萄糖缺乏/复氧诱导细胞凋亡的保护作用

背景背景:中枢神经系统中星形胶质细胞对神经元起重要的保护作用。据报道,一些抗氧化剂可以保护缺血/再灌注引起的星形胶质细胞功能障碍。肉桂鞣质B-1(Cinnamtannin B-1)是一种天然存在的A型原花青素,具有抗氧化作用。目的:研究肉桂鞣质B-1对脊髓星形胶质细胞的作用。方法:星形胶质细胞血清氧葡萄糖缺乏(OGSD)8 h后用或不用肉桂鞣质B-1进行复氧(R)。结果结果:肉桂鞣质B-1对OGSD/R诱导的星形胶质细胞凋亡具有保护作用,同时具有促进星形胶质细胞增殖的作用,而细胞外调节蛋白激酶(ERK)抑制剂逆转这种作用。结论结论:肉桂鞣质B-1通过ERK信号通路促进星形胶质细胞增殖,保护OGSD/R诱导的细胞凋亡。在中枢神经系统,肉桂鞣质B-1作为一种抗氧化剂对星形胶质细胞缺血/再灌注损伤具有保护作用。     

周围神经损伤后背根神经节及脊髓中神经胶质细胞、神经元TNF-α和TNF-αⅠ型受体表达上调的实验研究

该实验主要是应用双荧光免疫组化方法评定小鼠坐骨神经损伤后背根神经节及脊髓中胶质细胞、神经元细胞肿瘤坏死因子-α(TNF-α)及其受体(P55受体)表达变化。TNF-α是炎症反应中的主要介质,周围神经损伤后神经系统中的,TNF-α主要由巨噬细胞和雪旺细胞合成释放,也可由中枢神经系统中的星形胶质细胞和小胶质细胞释放,在中枢神经系统损伤的病理生理过程中发挥重要作用。     

前额叶皮质星形胶质细胞与认知功能

背景 前额叶皮质是大脑的高级思维中枢,具有整合信息形成意识的重要功能,此功能主要由神经元之间的相互联系完成.星形胶质细胞占中枢神经系统的绝大多数,近期已有大量研究证明神经元与星形胶质细胞存在相互作用,但具体机制尚不明确. 目的 为某些神经性疾病的治疗和麻醉药物的应用提供重要思路. 内容 从病理学、生理学及行为学方面综述前额叶皮质星形胶质细胞与认知功能的关系.一些以认知功能损伤为主要表现的大脑损伤性疾病中,大脑前额叶皮质发生特征性改变的同时该区域星形胶质细胞功能异常,最终表现为明显的意识障碍. 趋向 星形胶质细胞主要通过钙振荡参与神经元的调控功能,但其具体机制仍需进一步研究探讨.     

硫酸软骨素蛋白多糖在脊髓损伤病理机制中的作用

脊髓损伤（spinal cord injury,SCI）是由各种因素导致的脊髓损伤平面以下的感觉、运动及其他系统功能紊乱的中枢神经系统疾病。SCI不仅给患者带来严重的身心伤害,还会对家庭和社会造成巨大的经济负担。静息状态的星形胶质细胞被激活后转化为反应性星形胶质细胞（reactive astrocytes,RAS）是脊髓受损后所导致的一系列临床表现的病理基础。其主要作用是保护正常组织和神经元、减少损伤区域的水肿及炎性反应、促进损伤处血管再生。在脊髓损伤的早期,RAS可以通过减轻并修复损伤、保护血脑屏障、为神经元提供适宜的生存环境等方式对中枢神经系统起到保护作用。随着损伤的进展,神经元会出现脱髓鞘和突触连接的中断,加上氧化应激的产生,会导致细胞的凋亡、成纤维细胞的侵袭和炎症反应的持续发展,促使RAS不断分泌并上调损伤处硫酸软骨素蛋白多糖（chondroitin sulphate proteoglycans,CSPGs）的表达,最终在损伤区域的周围形成神经胶质瘢痕,以隔离损伤部位,阻止病变的进一步发展。所以在后期的损伤修复过程中,胶质瘢痕的形成不仅阻碍了轴突的延长,还严重影响了轴突的再生。因此,星形胶质细胞的活化和CSPGs的表达在SCI和修复过程中是一把双刃剑：损伤早期RAS可以防止炎症的扩大,避免更多细胞的损伤和坏死;后期会导致轴突再生的失败。所以在损伤后期消除RAS分泌的CSPGs所引发的胶质瘢痕,是SCI修复过程中的重要环节。笔者对CSPGs在SCI中的作用做一综述,为SCI的临床治疗提供参考。     

少突胶质细胞在脊髓损伤中的病理反应和作用

长期以来的研究认为少突胶质细胞的主要功能是形成中枢神经系统轴突髓鞘、营养和保护轴突,但近年研究发现少突胶质细胞尚有为中枢神经系统提供多种神经营养因子和生长因子、表达轴突生长抑制因子等作用,从而调节神经元、星形胶质细胞,甚至少突胶质细胞本身的生长、发育和存活.少突胶质细胞的凋亡、再生、髓鞘化和形成胶质瘢痕等反应在脊髓损伤继发性病理过程中扮演极其重要的角色,针对少突胶质细胞这一角色制定继发性脊髓损伤治疗新策略,有望成为解决这一医学难题的新切入点.该文就少突胶质细胞的生物学功能及其在脊髓损伤后的反应的研究进展作一综述.     

少突胶质前体细胞移植治疗脊髓损伤

脊髓损伤(spinal cord injuries,SCI)是常见的中枢神经系统损伤,可以造成感觉、运动等神经功能严重丧失。迄今为止,临床上尚无有效方法治疗脊髓损伤。以往研究表明,脊髓损伤后继发性病理生理变化不仅导致神经元丢失及轴突断裂,同时也影响着星形胶质细胞和少突胶质细胞(oligoden     

神经干细胞定向分化调控的研究进展

神经干细胞的发现不仅改变了中枢神经系统神经组织不能再生的传统观点，还为中枢神经系统损伤和疾病的研究提供了新的思路和途径。中枢神经系统内神经组织细胞包括神经元、星形胶质细胞、少突胶质细胞等多种细胞，其功能主要依赖神经元及其之间的神经信息传递，不同的神经元在形态结构上基本一致，但功能却各不相同。仅仅通过神经干细胞移植以期代替各种神经元的方法并不理想，较为理想的方法是在应用前根据靶组织类型对神经干细胞进行准确的定向分化诱导。     

促红细胞生成素与缺氧性脑损伤

促红细胞生成素(erythropoietin,EPO)是神经系统的一种神经营养因子和神经保护因子.EPO及其受体(erythro-poietin receptor,EPOR)在神经元、星形胶质细胞、少突胶质细胞、小胶质细胞和血管内皮细胞都可表达.脑组织缺氧缺血性损伤首先激活低氧诱发因子-1(HIF-1).后者促进EPO的分泌和表达,EPO和EPOR结合引发下游信号的级联反应表现出脑保护作用,其脑保护作用体现在抗凋亡、抗氧化、抗炎症等方面.众多动物实验和临床应用都证实重组人红细胞生成素(recombi-nant human erythmpoietin,rhEPO)对脑缺氧缺血性疾病具有脑保护作用.     

异丙酚和咪达唑仑可影响GABA_A受体所以可能对前脑缺血造成的神经元损害起保护作用

静脉全麻药物因能抑制大脑代谢、减少氧耗、减慢血流速度,降低颅内压、又能提高脑血管阻力等所以有脑保护作用。但脑缺血引起神经元逐步死亡不仅与能量代谢失常而且与功能丧失有关。当神经元细胞受损后常使中枢神经元抑制活动增强,例如γ-氨基丁酸能(GABA ergic)神经元,因为GABA_A/BZP(苯二氮(艹卓)类)受体复合体兴奋时,可引起氯离子进入神经元细胞,结果造成突触膜的超极化,从而抑制由于脑缺血引起兴奋性氨基酸的释放。近年的研究提示在中枢神经系统中GABA受体的不同亚型,其作用也不同。为此,作者通过研究异丙酚、咪达唑仑、戊巴比妥3种药物对GABA神经元系统的药理作用对前脑缺血引起损伤的脑保护作用。     

Dynamics of extravascular pulmonary water and intracranial pressure in patients with ischemic stroke

The objective of the present study was to examine the relationship among extravascular pulmonary water, intracranial and cerebral perfusion pressure, hemodynamic parameters (eg, cardiac index, system vascular resistance index), and brain stem function during acute ischemic stroke. The subjects were 17 comatose patients with ischemic stroke who were admitted to an intensive care unit. The results revealed an elevation in extravascular lung water in the absence of cardiac dysfunction. The absence of correlation between indices of brain vascular resistance and mean arterial pressure confirmed that a disturbance of cerebral blood flow was present. There was a correlation between auditory-evoked potential parameters and extravascular lung water during the study period. The correlation between auditory-evoked potentials and extravascular lung water may imply that ischemic brainstem injury plays a significant role in the development of increased pulmonary capillary permeability and the elevation of extravascular lung water. Brain stem injury is a cause of noncardiogenic lung edema in comatose patients following acute ischemic stroke.     

缺血性脑损伤与瞬时受体电位M通道的研究进展

缺血性脑血管病是临床常见病、多发病，其发病机制复杂。钙超载在缺血性脑损伤中起重要作用。瞬时受体电位M通道（transient receptor potential melastatin，TRPM）是位于细胞膜上的一类重要的非选择性阳离子通道超家族，对钙离子有较高的通透性，在缺血性脑损伤中起重要作用，对TRPM通道的研究将成为治疗缺血性脑损伤新的靶点。本文就胞内钙离子超载在缺血性脑损伤中的作用、TRPM通道及其参与的缺血性脑损伤的机制予以综述。     

Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke

Opinion statement Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 neuroprotective agents have reached randomized human clinical trials in focal ischemic stroke, but none has been unequivocally proven efficacious, despite successful preceding animal studies. The failed neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single agents alone. Although no neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective neuroprotective therapies to improve stroke outcome remain promising.     

Brain oxygenation and energy metabolism: part I-biological function and pathophysiology

CONTINUOUS OXYGEN DELIVERY and CO(2) clearance are paramount in the maintenance of normal brain function and tissue integrity. Under normal conditions, aerobic metabolism is the major source of energy in the brain, but this system may be compromised by the interruption of substrate delivery and disturbances in cerebral metabolism. These disruptions are major factors contributing to ischemic and hypoxic brain damage resulting from traumatic brain injury, stroke, and subarachnoid hemorrhage. There is evidence that mitochondrial function also is reduced after injury. Furthermore, early impairment of cerebral blood flow in patients with severe injury correlates with poor tissue oxygenation and may be an important parameter in secondary damage. Recent advances in brain tissue monitoring in the intensive care unit and operating room have made it possible to continuously measure tissue oxygen tension and temperature, as well as certain aspects of brain metabolism and neurochemistry. Therefore, it is important to understand the physiological process and the pathophysiology produced by these events. This is Part I of a two-part review that analyzes the physiology of cerebral oxygenation and metabolism as well as some of the pathological mechanisms involved in ischemic and traumatic brain injuries. Brain tissue monitoring techniques will be examined in the second article of this two-part series. To understand cerebral oxygenation, it is important to understand cerebral blood flow, energy production, ischemia, acidosis, generation of reactive oxygen species, and mitochondrial failure. These issues provide the basis of knowledge regarding brain bioenergetics and are important topics to understand when developing new approaches to patient care.     

Free radical scavengers and spin traps--therapeutic implications for ischemic stroke

Ischemic stroke comprises a complex cascade of pathophysiological mediators among which reactive oxygen species (ROS) play a pivotal role. Although oxidative stress as one major component contributing to ischemia-reperfusion injury has been thoroughly studied before, efficient treatment options for patients with ischemic stroke have so far not been transferred into clinical practice. In this review, the authors first describe some of the fundamental pathophysiological mechanisms that are involved in ROS generation after cerebral ischemia. Thereafter, antioxidant defense mechanisms and pharmacological manipulation of oxidative stress in various models of experimental cerebral ischemia are reviewed. The authors finally comment on recent clinical studies analyzing the effect of an antioxidative therapy after ischemic stroke and present a short outlook for further studies on ROS-mediated injury after stroke.     

Insulin-regulated aminopeptidase deficiency provides protection against ischemic stroke in mice

Recent studies have demonstrated that angiotensin IV (Ang IV) provides protection against brain injury caused by cerebral ischemia. Ang IV is a potent inhibitor of insulin-regulated aminopeptidase (IRAP). Therefore, we examined the effect of IRAP gene inactivation on neuroprotection following transient middle cerebral artery occlusion (MCAo) in mice. IRAP knockout mice and wild-type controls were subjected to 2?h of transient MCAo using the intraluminal filament technique. Twenty-four hours after reperfusion, neurological deficits of the stroke-induced mice were assessed and infarct volumes were measured by TTC staining. The cerebral infarct volume was significantly reduced in the IRAP knockout mice compared to wild-type littermates with corresponding improvement in neurological performance at 24?h post-ischemia. An increase in compensatory cerebral blood flow during MCAo was observed in the IRAP knockout animals with no differences in cerebral vascular anatomy detected. The current study demonstrates that deletion of the IRAP gene protects the brain from ischemic damage analogous to the effect of the IRAP inhibitor, Ang IV. This study indicates that IRAP is potentially a new therapeutic target for the development of treatment for ischemic stroke.     

Cerebral cortical neuron apoptosis after mild excitotoxic injury in vitro: different roles of mesencephalic and cortical astrocytes

OBJECTIVE: Increasing evidence supports the presence of neuronal apoptosis after ischemic or excitotoxic brain injury. Astrocytes, which exhibit significant regional differences in function, may exert a protective effect on neurons exposed to ischemic injury. We examined the effects of astrocytes derived from different regions of the central nervous system on neuronal apoptosis after mild excitotoxic injury in tissue culture. METHODS: Purified astrocyte cultures derived from P4 rat cerebral cortex or mesencephalon showed transient cell swelling but no cell death when exposed to 50 micromol/L glutamate for 5 minutes. When mixed neuronal/glial cocultures were exposed to the same glutamate dose, neuron death was observed. Necrotic and apoptotic cell death during 24 hours was examined using morphological criteria, nuclear staining, triphosphate nick end labeling, and trypan blue exclusion. RESULTS: We found that cortical neurons that elaborate a more extensive dendritic arbor when grown on homotypic astrocytes are more likely to undergo apoptosis than neurons with a limited dendritic arbor grown on heterotypic astrocytes. By contrast, a similar number of neurons undergo necrotic cell death. CONCLUSION: This finding may be associated with 1) increased vulnerability of neurons with a more elaborate dendrite structure to mild excitotoxic injury, or 2) regional differences in the ability of astrocytes to attenuate apoptosis.     

Involvement of mitogen-activated protein kinase pathways in expression of the water channel protein aquaporin-4 after ischemia in rat cortical astrocytes

Abstract Brain edema after ischemic brain injury is a key determinant of morbidity and mortality. Aquaporin-4 (AQP4) plays an important role in water transport in the central nervous system and is highly expressed in brain astrocytes. However, the AQP4 regulatory mechanisms are poorly understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs), which are involved in changes in osmolality, might mediate AQP4 expression in models of rat cortical astrocytes after ischemia. Increased levels of AQP4 in primary cultured astrocytes subjected to oxygen-glucose deprivation (OGD) and 2?h of reoxygenation were observed, after which they immediately decreased at 0?h of reoxygenation. Astrocytes exposed to OGD injury had significantly increased phosphorylation of three kinds of MAPKs. Treatment with SB203580, a selective p38 MAPK inhibitor, or SP600125, a selective c-Jun N-terminal kinase inhibitor, significantly attenuated the return of AQP4 to its normal level, and SB203580, but not SP600125, significantly decreased cell death. In an in vivo study, AQP4 expression was upregulated 1-3 days after reperfusion, which was consistent with the time course of p38 phosphorylation and activation, and decreased by the p38 inhibition after transient middle cerebral artery occlusion (MCAO). These results suggest that p38 MAPK may regulate AQP4 expression in cortical astrocytes after ischemic injury.     

Delayed biologic reactions to stereotactic charged-particle radiosurgery in the human brain.

Over 350 patients have been treated for inoperable intracranial arteriovenous malformations with charged-particle radiosurgery. Focussed accelerated helium ion beams derived from charged-particle cyclotrons are stereotactically directed into the brain to obliterate abnormal shunts. Treated patients demonstrate delayed changes in brain anatomy and function that occur months to years after radiosurgery. The underlying mechanisms of the brain's delayed reaction to charged-particle radiosurgery involve complex perturbations in cerebrovascular and metabolic function. This report describes the wide range of delayed reactions that may occur in the brain after radiosurgery, including hemodynamic changes, blood-brain barrier disruption and vasogenic edema, metabolic suppression, and parenchymal necrosis. These delayed reactions to injury in the brain involve potential target cells that include cerebral endothelial cells, oligodendroglia and astrocytes.     

谷氨酸转运体与缺血性脑损伤

背景 缺血性脑损伤严重威胁人类的生命健康,谷氨酸损伤在缺血性脑损伤的疾病进展中起重要作用,调控谷氨酸浓度对缺血性脑损伤的治疗具有重要意义.目的 探讨缺血性脑损伤与谷氨酸转运体的关系及多种预处理方法对谷氨酸转运体的影响,寻找一种缺血性脑损伤的治疗方法.内容 综述谷氨酸转运体的亚型、分布、结构和功能以及谷氨酸转运体与缺血性...