ERK1/2的激活参与七氟醚预处理对大鼠海马脑片缺氧无糖损伤的保护作用

目的观察ERK1/2的激活在七氟醚预处理对大鼠海马脑片缺氧无糖损伤保护中的作用。方法采用脑片灌流及电生理技术,细胞外记录海马CA1区的顺向群锋电位(OPS);利用2,3,5-三苯基氯化四氮唑(TTC)染色定量比色方法分析脑片损伤程度。结果用4%七氟醚预处理海马脑片,可延迟OPS的消失时间,提高复氧后OPS的恢复程度和恢复率。以ERK1/2特异性抑制剂PD98059(50μmol.L-1)预处理海马脑片,可以取消七氟醚的作用。单独使用PD98059对OPS无明显影响。七氟醚预处理组组织损伤百分率明显低于其它各组。结论ERK1/2的激活参与了七氟醚预处理对大鼠海马脑片缺氧无糖损伤的保护作用。     

七氟醚的心肌保护作用及进展

随着七氟醚在临床广泛使用,以及心脏内、外科的快速发展,有关七氟醚的药理学研究已经很广泛。七氟醚研究的热点集中之一就是其心肌保护作用的研究;因此心肌缺血再灌注损伤(myocardial ischemiareperfusion injury,MIRI)这一重要的病理生理过程也就成为心肌保护的热点。七氟醚预处理可以防止MIRI,但是这种预处理需要在缺血前实施,因而临床应用价值有限。然而,七氟醚后处理同样有很好的心     

七氟醚对培养心肌细胞缺氧损伤的保护作用

<正>七氟醚学作为新型的吸入麻醉药,其对心肌缺血再灌注动物及冠心患者有着明显的心肌保护作用[1,2]。本课题选用氰化钠造成培养心肌细胞缺氧(细胞内缺氧)模型,排除了血流动力学及其因素在缺氧损伤的影响,研究七氟醚对细胞缺氧损伤的直接作用,从而提示七氟醚对机体的非麻醉作用即抗损伤作用     

七氟醚对器官缺血再灌注的保护作用

缺血再灌注损伤在诸多疾病发生发展中发挥重要作用,对器官缺血再灌注损伤及其机制的研究已成为热点。七氟醚是新型卤组氟类吸入麻醉药,有研究报道七氟醚对心肌、大脑、肺、肾、肝等脏器缺血再灌注损伤有保护作用,并探讨其相关机制。本文对该方面研究进展作一综述。     

异氟醚对局灶性脑缺血/再灌注大鼠血管生成及Smad信号通路的影响

目的探讨异氟醚对脑缺血/再灌注大鼠血管生成的影响及其可能机制。方法健康成年♂SD大鼠40只,随机分为假手术组(Sham组)、缺血/再灌注组(I/R组)、异氟醚后处理组(ISO组)和异氟醚后处理+Smad3特异性抑制剂SIS3 HCl组(ISO+SIS3组)。线栓法建立大鼠大脑中动脉栓塞模型(MCAO),24 h后Zea-Longa法评估大鼠神经功能损伤,HE染色评估脑组织病理学损伤情况,尼氏染色评估缺血脑组织中健存神经元情况,TUNEL法评估脑组织凋亡情况,免疫荧光检测脑组织中VEGF蛋白和CD34蛋白的表达水平,Western blot对脑组织中p-Smad3、Smad3、VEGF和CD34进行定量分析。结果异氟醚能明显降低大鼠的神经行为学评分,减轻脑组织病理学损伤,增加缺血脑组织中健存神经元数量,减少损伤脑组织中的凋亡细胞,增强p-Smad3、VEGF和CD34蛋白的表达;Smad3抑制剂逆转了异氟醚的脑保护作用,加重了脑缺血/再灌注损伤,抑制p-Smad3、VEGF和CD34的蛋白表达。结论异氟醚能改善大鼠脑缺血/再灌注损伤,其保护机制与激活Smad信号通路,促进VEGF和CD34蛋白表达,进而促进血管生成有关。     

丙泊酚与七氟醚麻醉在肩关节脱位复位中的价值分析

目的比较丙泊酚和七氟醚麻醉在肩关节脱位复位中的应用价值。方法 2010年1月至2012年12月在本院骨科进行肩关节复位治疗的患者共82例,将所有患者随机分为3组,丙泊酚麻醉组28例,七氟醚麻醉组28例,臂丛神经麻醉组26例。比较三组患者疼痛评分、麻醉效果、复位期间生理指标及患者满意度。结果丙泊酚和七氟醚可以有效缓解患者疼痛,与臂丛神经麻醉比较差异有统计学意义(P<0.05),同时,丙泊酚和七氟醚对患者的麻醉效果优于臂丛神经麻醉,对呼吸等有一定的抑制作用,需要临床加强监控,患者满意度比较差异无统计学意义。结论丙泊酚和七氟醚对肩关节脱位复位患者的麻醉效果优于常规麻醉方法,但是临床使用时需要密切关注患者各项生理指标,根据患者实际情况,选择合适的麻醉方法。     

异丙酚和异氟醚对大鼠全脑缺血再灌注损伤的影响

目的：观察异丙酚和异氟醚对大鼠全脑缺血再灌注损伤的影响。方法：雄性SD大鼠随机分为2组，每组14只，分别在异丙酚和异氟醚麻醉下行全脑缺血15min，每组各7只于再灌注后30min和3d测SOD活性和MDA含量或海马CA1区存活神经元计数。结果：异丙酚组大鼠海马和皮层SOD活性显著高于异氟醚组（P〈0，01），MDA含量显著低于异氟醚组（P〈0．01）。异丙酚组海马CA1区成活神经元计数显著多于异氟醚组（P〈0．05）。结论：异丙酚对大鼠脑缺血再灌注损伤的保护作用强于异氟醚，其机制与其减轻氧自由基损伤有关。     

七氟醚对神经元缺氧损伤的保护及其作用机制

目的 观察七氟醚对大鼠海马神经元缺氧损伤的保护作用及其机制.方法 用原代培养的新生大鼠海马神经细胞建立缺氧模型,用MTT法测定神经元存活率.采用激光扫描共聚焦显微镜动态监测单个海马神经元[Ca2 ]i随缺氧或加入KCl前后的实时变化.结果 七氟醚在2MAC(肺泡气最小有效浓度),可降低神经元缺氧损伤时的细胞死亡率(P＜0.05).0.5～2MAC七氟醚能抑制缺氧及50 mmol/L KCl引起的[Ca2 ]i升高(P＜0.05).结论 七氟醚对离体大鼠海马神经元缺氧性损伤具有保护作用,其机制可能与七氟醚抑制缺氧引起[Ca2 ]i异常升高有关.     

SIRT1介导的七氟醚后处理对失血性休克复苏小鼠学习与记忆损伤的保护作用

目的探究沉默信息调节因子(silent information regulation 1,SIRT1)介导的凋亡相关通路在七氟醚后处理对失血性休克复苏小鼠海马神经元损伤中的保护作用。方法建立失血性休克与复苏小鼠模型,雄性C57BL/6J小鼠60只随机分为:假手术组(Sham组)、HSR组(Shock组)、七氟醚处理组(Sevo组)、七氟醚联合SIRT1特异性抑制剂处理组(EX527+Sevo组)以及EX527处理组(EX527组)。通过TTC染色法检测小鼠脑梗死体积,TUNEL染色法检测各组小鼠海马神经细胞的变化,水迷宫实验检测小鼠学习记忆能力,Western blot检测SIRT1和凋亡相关蛋白Bcl-2、Bax、Cleaved caspase-3的表达。结果造模小鼠在水迷宫检测中到达平台的潜伏期延长,在目标象限的运动距离减少,脑梗死体积增大,TUNEL染色阳性细胞数增多,SIRT1、Bcl-2蛋白表达降低,Bax、Cleaved-caspase3蛋白表达增加;七氟醚处理后改善了失血性休克与复苏小鼠的神经损伤情况,七氟醚与SIRT1抑制剂EX527联合处理后,七氟醚对失血性休克与复苏小鼠的神经损伤保护作用减弱。结论七氟醚可能通过SIRT1介导的凋亡相关通路发挥对失血性休克复苏引起的海马神经元损伤的保护作用。     

七氟醚对成人心脏手术体外循环中肺保护作用的Meta分析

摘要： 目的 用Meta分析的方法评估体外循环 （CPB） 下使用七氟醚对成人心脏手术患者的肺保护作用。方法 用计算机全面检索Cochrane library、 Embase、 PubMed、 Google scholar、 中国知网、 万方、 维普等数据库, 检索的关键词包括： 体外循环、 心脏手术、 肺保护、 七氟醚Meta分析。检索时间截止为2017年12月。获取公开发表的有关在CPB下七氟醚对肺保护的随机对照试验 （RCT） 的文献。由2位研究者单独对入选文献进行质量评价和数据提取, 利用 RevMan5.3进行Meta分析。结果 共入选11篇RCT文献, 440例患者, 其中七氟醚组220例、 全凭静脉麻醉 （TIVA） 组 220例。结果显示, 与TIVA组相比, CPB中使用七氟醚可以有效降低患者血液中白细胞介素 （IL） -6 （P=0.005） 和IL-8 浓度 （P=0.01）, 减少术后气管插管时间 （P＜0.001）。但是2组间肿瘤坏死因子-α （TNF-α） 浓度 （P=0.19）、 肺泡-动脉血氧分压差 ［P（A-a） O2 ］（P=0.68） 和氧合指数OI （P=0.31） 差异无统计学意义。结论 在CPB期间使用七氟醚能够有效降低患者血液中部分炎性因子的浓度, 减少术后气管插管时间, 但尚无足够证据证明在CPB中用七氟醚具有确切的肺保护作用。     

Nimesulide as a promising neuroprotectant in brain ischemia: new experimental evidences.

Nimesulide is a preferential inhibitor of cyclooxygenase-2 (COX-2) and it is one of the most prescribed non-steroidal anti-inflammatory drugs (NSAID) worldwide. Nimesulide was recently shown to have neuroprotective properties in animal models of acute neurologic injury. In particular, nimesulide is highly effective in reducing ischemic brain injury. This neuroprotective efficacy has been demonstrated in animal models of transient and permanent focal cerebral ischemia, global brain ischemia, embolic stroke, and chronic cerebral hypoperfusion. Nimesulide has been shown to reduce infarction, improve neurological function, attenuate blood-brain barrier disruption and edema, and reduce leukocyte infiltration into the ischemic brain. These beneficial effects have been observed even when the first treatment is given several hours after the onset of ischemia, demonstrating the wide therapeutic time window for nimesulide's neuroprotection. This is of great relevance since most stroke patients reach the emergency room several hours after the onset of symptoms, a time at which most medical interventions are not effective. In addition, nimesulide produces a long-lasting neuroprotection. This is of importance since some 'neuroprotective' compounds only produce a delay in cell death, and not a permanent protection. Its several mechanisms of action in neuroprotection make nimesulide a desirable and promising candidate as therapy for acute brain ischemia. This article reviews recent knowledge on the effects of nimesulide against brain injury, with particular emphasis in cerebral ischemia, and makes a critical appraisal of its therapeutic potential in the management of patients with brain ischemia.     

Current state on development of neuroprotective agents for cerebral ischemia

The improvement of decreased cerebral blood flow using thrombolytic agents, anti-thrombin drugs, and antiplatelet drugs has been essential for acute ischemic stroke. Edaravone, a free radical scavenger, has been commercially available as a novel neuroprotective agent for ischemic stroke in Japan from 2001. The appearance of a neuroprotective agent implies that therapeutic strategy can be expanded through a combination with thrombolysis. In the previous development, several cases have reported that neuroprotective compounds failed in clinical trials. However, recent studies have clarified that the cerebral ischemia induced the neuronal cell death by mediating multiple mechanisms with necrosis and/or apoptosis. The cytotoxicity derived from the NO/peroxynitrite/free radical generating system, one of intracellular Ca2+ signaling, is a typical event in ischemic injury, which is protected by edaravone. Furthermore, it is suggested that suppression of excessively activated voltage-dependent Na+ and Ca2+ channels is effective as a strategy for neuroprotection, since abnormal excitatory stimuli in the neuronal network result in the cerebral infarction. The development of several compounds having different mechanisms of action for acute stroke is in progress. It is therefore prospected that the various novel neuroprotective agents will be provided for assuring the option of therapeutic strategy, since the reinforcement of medical stroke care including diagnosis contributes to the prolongation of the therapeutic time window.     

Prophylactic neuroprotection

Ischemic brain injury can be anticipated in a number of clinical settings such as procedures associated with a high-risk for stroke, patients with transient ischemic attacks or minor strokes who are at substantial risk for early recurrence and patients with multiple vascular risk factors with an enhanced risk for ischemic stroke over many years. In such high-risk settings, it may be possible to employ neuroprotective drugs prophylactically to reduce the extent and clinical consequences of ischemic events. The concept of prophylactic neuroprotection can be envisioned for varying time periods and with a variety of drug classes depending upon the target population. This review will focus on which target populations should be considered for prophylactic neuroprotection trials and which drugs might be used in such trials.     

Neuroprotection by alpha 2-adrenergic agonists in cerebral ischemia

Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2-adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury.     

Neuroprotection in cerebrovascular disease

The role of neuroprotection in the management of acute cerebrovascular disease is reviewed. Neuroprotection is a valuable adjunct to thrombolytic therapy in acute cerebral ischaemia. Various pharmacological approaches for neuroprotection are based on the current knowledge of molecular events in the pathophysiology of cerebral ischaemia. Reperfusion injury following restitution of circulation is also considered to be mediated by free radicals. Various strategies include free radical scavengers, anti-excitotoxic agents, apoptosis (programmed cell death) inhibitors, anti-inflammatory agents, metal ion chelators, ion channel modulatory, antisense oligonucleotides and gene therapy. The various agents aim to prevent the progression of ischaemic cascade therefore reducing brain damage and some of these intervene at more than one point in the ischaemic cascade. Neuroprotection is considered as an adjunct to therapies designed to improve cerebral circulation such as thrombolytic agents for arterial thrombosis. Clinical effectiveness of some of the strategies has not be proven in clinical trials, some of which had to be abandoned due to adverse effects outweighing the beneficial effects. Efforts to develop new neuroprotective agents continue and prospects for the introduction of an effective neuroprotective agent(s) in the next few years are good. Apart from acute cerebrovascular disease, neuroprotective therapy has a role in preventing cerebral ischaemia in high risk cardiovascular procedures as well as in neurodegenerative disorders which has some common pathomechanisms with cerebrovascular disease. Currently, the most promising agents are free radical scavengers. In the near future, gene therapy approaches are likely to prove more effective in neuroprotection.     

Do statins afford neuroprotection in patients with cerebral ischaemia and stroke?

An emerging body of evidence indicates that beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or 'statins', provide neuroprotection in addition to reducing ischaemic stroke. Statins reduce the incidence of ischaemic stroke by stabilising atherosclerotic plaques in the precerebral vasculature and through antithrombotic actions, and the neuroprotective effects of statins may confer significant clinical benefit. Some of these neuroprotective effects are likely to be cholesterol independent and mediated by the interruption of isoprenoid biosynthesis. Therapy with statins may modulate endothelial function and preserve blood flow to regions exposed to an ischaemic insult. In particular, statin-mediated preservation of endothelial nitric oxide synthase activity in cerebral vasculature, especially in the ischaemic penumbra, may limit neurological deficit. Moreover, putative anti-inflammatory and antioxidant properties of statins may confer additional neuroprotection. Further large clinical trials are necessary to address the role of statin therapy in the primary prevention of stroke, small vessel cerebrovascular disease and vascular dementia.     

Adenosine and Stroke: Maximizing the Therapeutic Potential of Adenosine as a Prophylactic and Acute Neuroprotectant

Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant.Key Words: Adenosine, adenosine receptors, cerebral ischemia, neuroprotection, preconditioning, stroke, treatment.     

Eriodictyol-7-O-glucoside activates Nrf2 and protects against cerebral ischemic injury

Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependent genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke.     

Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia

Ischemic stroke is a devastating disease with a complex pathophysiology. Animal modeling of ischemic stroke serves as an indispensable tool first to investigate mechanisms of ischemic cerebral injury, secondly to develop novel antiischemic regimens. Most of the stroke models are carried on rodents. Each model has its particular strengths and weaknesses. Mimicking all aspects of human stroke in one animal model is not possible since ischemic stroke is itself a very heterogeneous disorder. Experimental ischemic stroke models contribute to our understanding of the events occurring in ischemic and reperfused brain. Major approaches developed to treat acute ischemic stroke fall into two categories, thrombolysis and neuroprotection. Trials aimed to evaluate effectiveness of recombinant tissue-type plasminogen activator in longer time windows with finer selection of patients based on magnetic resonance imaging tools and trials of novel recanalization methods are ongoing. Despite the failure of most neuroprotective drugs during the last two decades, there are good chances to soon have effective neuroprotectives with the help of improved preclinical testing and clinical trial design. In this article, we focus on various rodent animal models, pathogenic mechanisms, and promising therapeutic approaches of ischemic stroke.     

Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury

Recanalization and neuroprotection have been mainly targeted for the specific treatment of acute ischemic stroke. Free radicals play a crucial role in brain ischemic injury by exacerbating membrane damage through peroxidation of unsaturated fatty acids of cell membrane, leading to neuronal death and brain edema. Free radicals have been implicated in stroke pathophysiology as pivotal contributors to cell injury. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a novel potent free radical scavenger that has been clinically used to reduce the neuronal damage following ischemic stroke. Edaravone exerts neuroprotective effects by inhibiting endothelial injury and by ameliorating neuronal damage in brain ischemia. Edaravone provides the desirable features of NOS: it increases eNOS (beneficial NOS for rescuing ischemic stroke) and decreases nNOS and iNOS (detrimental NOS). Post- reperfusion brain edema and hemorrhagic events induced by thrombolytic therapy may be reduced by edaravone pretreatment. Increased productions of superoxide and NO in the brain after reperfusion and a concomitant surge in oxygen free radicals with increased NO during recirculation lead to formation of peroxynitrite, a superpotent radical. Edaravone, which inhibits oxidation and enhances NO production derived from increased eNOS expression, may improve and conserve cerebral blood flow without peroxynitrite generation during reperfusion. Clinical experience with edaravone suggests that this drug has a wide therapeutic time window. The combination therapy (a thrombolytic plus edaravone) is likely to target brain edema, reduce stroke death and improve the recovery from neurological deficits in stoke patients.