肢体缺血预适应的脑保护作用机制

缺血预适应(IPC)指机体预先经过一次或多次短暂非致死性刺激后,提高抵御未来严重甚至致死性缺血打击的耐受能力.其作为一种激活机体自身内源性保护机制来对抗脑缺血损伤的手段,近年来逐渐引起了学者的兴趣.肢体缺血预适应(LIP)是通过反复捆绑止血带间断阻断其血流供应来实现的,虽然LIP的保护作用在心肌缺血领域已较为清楚[1],但其对脑缺血的保护作用研究较少,现就LIP的脑保护作用机制综述如下.     

缺血预适应的神经保护机制

缺血预适应（ischemic preconditioning，IPC）是指1次或多次短暂的缺血事件发生后可激发机体内源性保护机制，从而减轻后续严重缺血事件引起的损伤，这种现象亦称为缺血耐受（ischemic tolerance，IT）。该现象是1986年Murry等在心肌组织中首先发现。之后，人们发现脑、肝、肾及小肠同样存在这种现象。在过去的10余年中针对脑缺血的预适应现象已进行了大量的实验研究。     

脑缺血耐受机制的研究进展

缺血耐受 (ＩＴ)是指器官或组织经受短暂的亚致死性的缺血 (缺血预处理 ,ＩＰ)后 ,在特定的时间内对再次的长时间的致死性的缺血产生耐受的现象。其形成机制涉及到细胞信号转导和相应的介质、受体、基因及其表达产物等的复杂变化。其发现和研究为临床脑保护治疗方法的探索提供了新的线索。现就近年来研究的热点问题综述如下。1　概述ＩＴ首先在心脏中发现 ,后发现在脑、肝脏、肾脏、小肠、肺、骨骼肌等器官和组织中广泛存在。最初在短暂缺血后发现ＩＴ现象 ,后来发现有多种亚致死刺激可引起脑ＩＴ ,是一种非特异性的自我保护现象。在体外培…     

缺血/低氧预适应的脑保护作用

缺血/低氧预适应(ischaemic/hypoxic preconditioning)是指机体预先受一次或多次短暂、非致死性缺血/低氧刺激,再恢复常态后,从而获得的对更严重甚至致死性缺血或缺氧的耐受性.     

远端缺血处理在脑保护作用的临床应用现状及前景

远端缺血处理是指给予一种器官或组织反复、短暂、非致死性的缺血性刺激,而使远端器官耐受并降低后续的缺血损伤。在远隔缺血处理研究中,远端肢体缺血处理操作方便简单且安全性高,发现其对脑、心脏、肝、肺、肾脏等重要器官均有一定的保护作用,在临床广泛应用。本文现就远端缺血处理在脑保护作用和临床应用现状和前景作一阐述。     

应用缺血修饰白蛋白评价缺血预适应对脑血管保护作用

目的应用缺血修饰白蛋白评价缺血预处理对脑血管保护作用的疗效及安全性。方法将急性脑梗死患者根据年龄分为中年组(60岁)和老年组(≥60岁),每组随机分为缺血预适应组及对照组。所有患者入院后第2天测定缺血修饰白蛋白,均给予同样的药物治疗,缺血预适应组在发病后第8天开始缺血预处理。如果患者脑血管病复发终止试验。300d内脑梗死无复发的患者在第301天测定缺铁修饰白蛋白。结果中年组和老年组缺血预适应均能降低脑梗死的复发率及延长复发时间,降低再梗死的缺血修饰白蛋白水平。结论缺血预适应能够确切保护脑血管,减少后续梗死造成的损害。     

远隔缺血适应脑保护的临床应用实施方案及安全性的研究进展

远隔缺血适应治疗是通过对远隔非重要器官进行短暂的、非致死性的缺血-再灌注,从而保护对缺血敏感的重要器官(如心、脑、肾等)的一种内源性保护机制。本文对远隔缺血适应脑保护的临床应用实施方案及安全性进展进行了综述,为临床开展该方面研究提供借鉴。     

神经营养因子与脑缺血预处理

脑缺血预处理(BIP)是指对脑预先进行一次或多次短暂的非致死性缺血刺激后,机体获得对更严重甚至致死性脑缺血的耐受性。BIP能提高脑组织对缺血的耐受性,本文就近年来有关神经营养因子在缺血预处理后表达及表达后的产物对神经元是否有保护作用以及可能的作用机制作一综述。     

短暂性脑缺血与缺血耐受

短暂性脑缺血发作（TIA）是指大脑暂时性的缺血现象，24h内其神经功能的缺损会完全恢复。缺血耐受是指短暂的脑缺血可降低1～7d后再次持续性的导致细胞死亡的缺血所产生的损伤作用，这种现象最早由日本学者在1990年阐述。目前认为短暂性脑缺血发作可使中枢神经产生缺血耐受，从而保护神经细胞，现将这一作用及机制做一综述。     

低氧诱导因子-1与脑缺血耐受

脑缺血耐受 (cerebralischemictoler ance,CIT)是指一次或多次短暂 (亚致死 )缺血作为一种损伤性应激原 ,通过调动机体内源性保护机制而提高脑组织耐受后续较长时间 (致死 )缺血能力的现象。在严重脑缺血之前给予各种保护性的干预措施称为预处理 (precondition ing)。1990年Kitagawa等[1] 首先在沙土鼠全脑缺血模型中发现 ,短暂的全脑缺血后再灌注对随后更长时间的缺血可产生耐受性。临床研究也证实了脑缺血耐受的存在。Moncayo等[2 ] 对 2 4 92例首次发生脑梗死的患者进行研究 ,发现短暂性脑缺血发作 (transientischemicat tack ,TIA)…     

缺血预处理后海马CA1区反应性星形胶质细胞增生与迟发性神经元缺血耐受性的关系

目的 探讨缺血预处理后海马CA1区反应性星形胶质细胞增生与迟发性神经元缺血耐受性的关系。方法 实验动物被随机分为手术组、缺血组、预缺血组、预缺血后再缺血组。阴断沙土鼠双侧颈总动脉造成前脑缺血模型。采用细胞特异性抗原胶质纤维酸性蛋白（GFAP）免疫组化法标记星形胶质细胞。结果 预缺血后1－7天,海马CA1区GFAP阳性的星形胶质细胞数轻度增加,至28天时增生非常显著（P＜0．01）。预缺血后1－7天再缺血,海马CA1区存活正常神经元数逐渐下降,预缺血后28天再缺血又显著增加（P＜0．01）。结论 缺血预处理后,神经元可出现迟发性缺血耐受,反应性星形胶质细胞增生可能起了重要作用。     

Induction of NADPH-diaphorase activity in the hippocampus in a rat model of cerebral ischemia and ischemic tolerance

Preconditioning of the brain with sublethal ischemia induces tolerance to subsequent lethal periods of ischemia (ischemic tolerance). In this study, we used NADPH-diaphorase histochemistry to investigate the postischemic changes of nitric oxide synthase (NOS) in the hippocampus in a rat model of cerebral ischemia and ischemic tolerance. Forebrain ischemia was induced by 4-vessel occlusion for 3 min as an ischemic preconditioning. Three days after the preconditioning or sham operation, second ischemia was induced for 6 min. A transient increase in NADPH-diaphorase activity, beginning after 2 h and maximal after 1 day, was observed in CA1 pyramidal neurons of rats subjected to 3 min of preconditioning ischemia as well as 6 min of subsequent ischemia both with and without preconditioning. In addition, expression of NADPH-diaphorase activity was seen in reactive glial cells in the damaged CA1 region of animals subjected to 6 min of ischemia without preconditioning. Thus, direct involvement of increased NADPH-diaphorase activity in ischemic tolerance was not suggested because the increased NADPH-diaphorase activity preceded the induction of ischemic tolerance which takes place 1–7 days after preconditioning. However, the present findings suggest that the induction of neuronal NADPH-diaphorase activity occurs in response to cerebral ischemia.     

脑缺血耐受与细胞凋亡及p53、p21、Bax表达关系的实验研究

目的　探讨大鼠局灶性缺血预处理的脑保护作用与细胞凋亡及凋亡相关因子p5 3、p2 1和Bax的关系。方法　采用线栓法阻塞大鼠大脑中动脉造成脑缺血预处理和致死性缺血模型 ,图像分析测算相对梗死体积 ,使用TUNEL染色标记神经细胞凋亡 ,免疫组化染色观察p5 3、p2 1和Bax蛋白表达。结果　与致死缺血组比较 ,缺血预处理组梗死体积减少 4 6 % (P <0 0 5 ) ,半暗区TUNEL阳性细胞数和p5 3阳性细胞数均明显降低 (均P <0 0 5 ) ,p2 1和Bax阳性细胞数无显著变化 (均P >0 0 5 )。结论　缺血预处理可能通过抑制严重缺血后p5 3表达 ,减轻神经细胞凋亡 ,发挥脑保护作用。p2 1和Bax在脑缺血耐受形成中可能不起重要作用。     

Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonist.

Two types of ischemic tolerance in the brain, rapid and delayed, have been reported in terms of the interval between the conditioning and test insults. Although many reports showed that delayed-phase neuroprotection evoked by preconditioning is evident after 1 week or longer, there have been a few investigations about rapidly induced tolerance, and the reported neuroprotective effects become ambiguous 7 days after the insults. The authors examined whether this rapid ischemic tolerance exists after 7 days of reperfusion in a rat focal ischemic model, and investigated modulating effects of the adenosine A 1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine). Preconditioning with 30 minutes of middle cerebral artery occlusion reduced infarct volume 7 days after 180 minutes of subsequent focal ischemia given after 1-hour reperfusion. The rapid preconditioning also improved neurologic outcome. These beneficial effects were attenuated by pretreatment of 0.1 mg/kg DPCPX, which did not influence the infarct volume after conditioning (30 minutes) or test (180 minutes) ischemia when given alone. The results show that preconditioning with a brief focal ischemia induces rapid tolerance to a subsequent severe ischemic insult, the effect of which is still present after 7 days of reperfusion, and that the rapid ischemic tolerance is possibly mediated through an adenosine A 1 receptor-related mechanism.     

缺血预处理对大鼠脑缺血再灌注后ICAM-1表达的影响

目的 通过研究脑缺血预处理对大鼠脑缺血再灌注后细胞间粘附分子-1(Intowellular adhesion molecule-1，ICAM-1)表达及多形核白细胞(Ploymorphonuclear leukocytes，PMNLs)浸润变化的影响．探讨预处理的延迟保护作用机制。方法采用四血管阻断法建立大鼠全脑-全脑缺血预处理模型。应用HE染色和免疫组化染色技术，观察脑缺血预处理后ICAM-1表达及多形核白细胞浸润的变化。结果(1)脑缺血再灌注后ICAM-1表达的阳性血管数量、PMNLs浸润数量均明显增加；(2)脑缺血预处理可明显减少缺血再灌注后ICAM-1的表达阳性血管数及PMNLs的浸润数量。结论一次性缺血预处理3min后48h可以少再次长时间缺血(30min)／再灌注(24h)的ICAM-1的表达和多形核白细胞浸润。ICAM-表达的下调和PMNLs浸润减少参与缺血预处理的保护作用。     

Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice.

In a process called ischemic preconditioning, a brief, sublethal ischemic insult protects tissue from subsequent, more severe injury. There have been no reports of rapidly induced ischemic preconditioning. The authors sought to develop a model of cerebral ischemic preconditioning in the mouse that can be applied to transgenic and knockout animals. They found that brief middle cerebral artery (MCA) occlusion only minutes before a severe ischemic insult can induce protection from that insult. Here the investigators describe a mouse model of preconditioning using intraluminal MCA occlusion as both the conditioning and the test stimulus. One or three 5-minute episodes of ischemia given 30 minutes before MCA occlusion for 1 or 24 hours (permanent occlusion) confer significant protection as assessed by infarct volume measurements 24 hours later.     

Hypothermic preconditioning induces rapid tolerance to focal ischemic injury in the rat

Stressful, preconditioning stimuli can elicit rapid and delayed forms of tolerance to ischemic injury. The identification and characterization of preconditioning stimuli that are effective, but relatively benign, could enhance the clinical applicability of induced tolerance. This study examines the efficacy of brief hypothermia as a preconditioning stimulus for inducing rapid tolerance. Rats were administered hypothermic preconditioning or sham preconditioning and after an interval of 20-120 min were subjected to transient focal ischemia using a three-vessel occlusion model. The volume of cerebral infarction was measured 24 h or 7 days after ischemia. In other experiments, the depth or duration of the hypothermic stimulus was manipulated, or a protein synthesis inhibitor (anisomycin) was administered. Twenty minutes of hypothermia delivered 20 or 60 (but not 120) min prior to ischemia significantly reduces cerebral infarction. The magnitude of protection is enhanced with deeper levels of hypothermia, but is not affected by increasing the duration of the hypothermic stimulus. Treatment with a protein synthesis inhibitor does not block the induction of rapid tolerance. Hypothermic preconditioning elicits a rapid form of tolerance to focal ischemic injury. Unlike delayed tolerance induced by hypothermia, rapid tolerance is not dependent on either de novo protein synthesis or the duration of the preconditioning stimulus. These findings suggest that the mechanisms underlying rapid and delayed tolerance induced by hypothermia differ fundamentally. Brief hypothermia could provide a rapid means of inducing transient tissue protection in the context of predictable ischemic events.     

Changes in protein tyrosine phosphorylation in the rat brain after cerebral ischemia in a model of ischemic tolerance.

A brief period of sublethal cerebral ischemia, followed by several days of recovery, renders the brain resistant to a subsequent lethal ischemic insult, a phenomenon termed ischemic preconditioning or tolerance. Ischemic tolerance was established in the rat two-vessel occlusion model of ischemia, induced by occlusion of both carotid arteries in combination with hypotension. Ischemic preconditioning (3 minutes) provided maximal neuroprotection when induced 2 days prior to a lethal ischemic insult of 9-minute duration. Neuroprotection persisted for at least 8 weeks. Since neurotransmission has been implicated in ischemic cell death, the effect of ischemic preconditioning on tyrosine phosphorylation of proteins and on the levels of glutamate receptor subunits in hippocampus and neocortex was studied. Regional levels of tyrosine phosphorylation of proteins in general and the N-methyl-D-aspartate receptor subunit NR2 in particular are markedly enhanced after ischemia in nonconditioned brains, in both the synaptosomal fraction and the whole-tissue homogenate of rat neocortex and hippocampus, but recover to control levels only in the preconditioned brain. Ischemic preconditioning selectively induces a decrease in the levels of the NR2A and NR2B subunits and a modest decrease in the levels of NR1 subunit proteins in the synaptosomal fraction of the neocortex but not hippocampus after the second lethal ischemia. It was concluded that ischemic preconditioning prevents a persistent change in cell signaling as evidenced by the tyrosine phosphorylation of proteins after the second lethal ischemic insult, which may abrogate the activation of detrimental cellular processes leading to cell death.     

Neuroprotective effects of ischemic preconditioning on hippocampal CA1 pyramidal neurons through maintaining calbindin D28k immunoreactivity following subsequent transient cerebral ischemia

Ischemic preconditioning elicited by a non-fatal brief occlusion of blood flow has been applied for an experimental therapeutic strategy against a subsequent fatal ischemic insult. In this study, we investi-gated the neuroprotective effects of ischemic preconditioning (2-minute transient cerebral ischemia) on calbindin D28k immunoreactivity in the gerbil hippocampal CA1 area following a subsequent fatal tran-sient ischemic insult (5-minute transient cerebral ischemia). A large number of pyramidal neurons in the hippocampal CA1 area died 4 days after 5-minute transient cerebral ischemia. Ischemic preconditioning reduced the death of pyramidal neurons in the hippocampal CA1 area. Calbindin D28k immunoreactivity was greatly attenuated at 2 days after 5-minute transient cerebral ischemia and it was hardly detected at 5 days post-ischemia. Ischemic preconditioning maintained calbindin D28k immunoreactivity after transient cerebral ischemia. These findings suggest that ischemic preconditioning can attenuate transient cerebral ischemia-caused damage to the pyramidal neurons in the hippocampal CA1 area through maintaining cal-bindin D28k immunoreactivity.