脑缺血预处理与脑缺血耐受的研究进展

1990年Kitagawa等发现全脑1次短暂缺血即缺血预处理后并未引起明显的脑神经损伤，但对再次致死性缺血损伤产生了明显的保护作用，这种保护作用即为脑缺血耐受：这一现象立即引起了广泛关注，随着研究的进展，发现通过其他方法也可以诱导脑缺血耐受，弱的损伤如轻度低氧、低温、高压氧、扩散性抑制等刺激均可引发神经细胞对缺血产生耐受。现对缺血预处理诱导脑缺血耐受的研究进展综述如下。     

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)…     

脑缺血耐受

人们一直在寻找预防和治疗脑缺血的方法。近年发现脑缺血预处理可以诱导脑缺血耐受。本文阐述脑缺血耐受的模型及可能的产生机制。     

3-硝基丙酸预处理对大鼠局灶性脑缺血神经元凋亡的影响

目的 :探讨小剂量线粒体毒素 3 硝基丙酸 ( 3 nitoppropionicacid ,3 NPA)预处理对大鼠局灶性脑缺血脑梗死体积 ,脑缺血半暗带神经元凋亡的影响 ,阐明 3 NPA预处理诱导脑缺血耐受的机制。方法 :大鼠腹腔注射 3 NPA 3d后制作大脑中动脉闭塞模型 ,采用TTC染色、TUNEL法和流式细胞术 ,观察 3 NPA预处理对缺血 2h再灌注 2 4h脑梗死体积、神经元凋亡的影响。结果 :缺血 2h再灌注 2 4h ,3 NPA预处理组脑梗死体积变小 ,神经元凋亡减少 ,与对照组比有显著性差异。结论 :3 NPA预处理可以诱导脑缺血耐受 ,抑制神经元凋亡可能是其机制之一     

基质金属蛋白酶-9在缺血性脑损伤和脑缺血耐受中的表达

基质金属蛋白酶-9(MMP-9)在脑缺血时可以通过降解基底膜及紧密连接破坏血脑屏障,从而导致脑缺血后继发性脑水肿和脑出血。脑梗死时MMP-9表达增强,病情加重;而脑缺血预处理可诱导MMP-9表达下调,提示MMP-9可能参与脑缺血耐受形成的过程。本文就MMP-9在缺血性脑损伤和脑缺血耐受中表达的研究进展进行综述。     

短暂性脑缺血发作对脑缺血耐受的影响

目的 探讨短暂性脑缺血发作（TIA）在脑缺血耐受方面的临床意义。方法 选择30例TIA后72h内发生脑梗死的患者为试验组（TIA组）,并随机选择30例无TIA史的脑梗死患者作对照组。结果 TIA组和脑梗死组在脑梗死体积、治疗前与治疗后15d,30d,90d的欧洲卒中量表（ESS）评分方面存在统计学差异（8.2 ml vs 10.6 ml;62±22 vs 58±24;70±28 vs 66±32;80±20 vs 76±24;82±18 vs 77±23; P均<0.05）。结论 TIA后发生脑梗死对减轻脑细胞损伤有一定临床意义。     

伴短暂性脑缺血发作的脑梗死20例临床分析

目的探讨短暂性脑缺血发作(TIA)在脑梗死中的临床意义。方法回顾性分析2001-06~2004-09本院的20例有TIA的脑梗死患者的临床资料(设为观察组),并设与之相匹配的20例无TIA的脑梗死患者为对照组。结果观察组、对照组患者治愈率相比有显著性差异(P<0.01),两组神经功能缺损评分相比有显著性差异(P<0.01)。结论TIA诱导神经组织产生缺血耐受即缺血预处理,使大脑通过内源性或血管保护机制以对抗随后的严重损害,起到神经保护作用。     

两次线栓法构建脑缺血耐受模型大鼠血脑屏障通透性改变与基质金属蛋白酶9的表达☆

背景：诸多研究证实,短暂性脑缺血预处理可诱导脑缺血耐受。然而,脑缺血耐受的内源性保护机制尚未明确。 目的：观察脑缺血预处理诱导脑缺血耐受大鼠再灌注不同时间窗血脑屏障通透性改变及基质金属蛋白酶9表达的变化。 方法：将Wistar大鼠随机分为3组,缺血预处理组采用线栓法阻塞大脑中动脉10 min建立局灶性缺血预处理模型,分别在缺血预处理后1,3,7,14,21 d进行再次缺血2 h;模型组不进行缺血预处理,假手术组不阻塞血管。于再灌注22 h进行神经功能检测,采用TTC染色测定脑梗死体积,通过测定渗出血管外的伊文思蓝含量来评价血脑屏障通透性的变化,免疫组织化学和原位杂交法检测基质金属蛋白酶9蛋白及mRNA的表达。 结果与结论：与模型组比较,缺血预处理组1,3,7 d亚组的神经功能评分、脑梗死体积、血脑屏障通透性、脑含水量以及基质金属蛋白酶9蛋白和mRNA表达均明显减小/降低(P < 0.05或P < 0.01),其中以3 d亚组降低最为明显。提示缺血预处理诱导了脑缺血耐受,预缺血诱导的血脑屏障通透性改变以及基质金属蛋白酶9表达减低在脑缺血耐受中发挥重要作用。     

局灶性脑缺血耐受和星形胶质细胞反应

目的　研究短暂性局灶性脑缺血预处理对永久性局灶性脑缺血的保护作用 ,及最佳预处理时间剂量 ,并探讨星形胶质细胞在脑缺血耐受中的反应。方法　采用开颅方法阻断大鼠大脑中动脉 ,通过观察大鼠脑梗死后神经功能损伤状况、脑梗死体积分析及病理形态学变化 ,评价不同的缺血预处理时间剂量 (10分钟、2 0分钟、30分钟 )对永久性局灶性脑缺血的保护作用。采用胶质纤维酸性蛋白 (GFAP)免疫组化法观察星形胶质细胞在脑缺血耐受中的反应。结果　与对照组相比 ,缺血预处理 2 0分钟未引起明显的神经元损伤 ,但使永久性局灶性脑缺血后神经功能损伤减轻 ,梗死体积明显减小 (P <0 .0 1)。免疫组化显示 ,2 0分钟缺血预处理组及重复缺血组星形胶质细胞在损伤预处理侧广泛激活。结论　 2 0分钟局灶性脑缺血预处理能够有效诱导脑缺血耐受。星形胶质细胞的激活可能与脑缺血耐受中神经元的存活相关。     

Bcl-2、Bax蛋白产物在脑缺血耐受中的表达及前列腺素E1的干预作用

目的探讨大鼠脑缺血时凋亡相关基因Bcl-2、Bax蛋白的表达与脑缺血耐受的关系及前列腺素E1 (PGE1)对脑缺血耐受的影响。方法采用大鼠全脑-局灶脑缺血耐受模型。观察预缺血组、PGE1组在大脑中动脉梗死2h再灌注(MCAO)24h后神经行为评分、脑梗死体积、Bcl-2、Bax蛋白表达和TUNEL、流式细胞仪检测神经细胞凋亡。结果MCAO后24h,PGE1组的神经行为评分、脑梗死体积、Bax蛋白表达更少,Bcl-2蛋白表达较高,神经细胞凋亡降低。结论预缺血及PGE1预处理后,使Bax蛋白表达减少,Bcl-2蛋白表达增高能够诱导脑缺血耐受,且PGE1的作用优于预缺血。     

Relevance of transient ischemic attack to early neurological recovery after nonlacunar ischemic stroke

BACKGROUND: We hypothesized that previous transient ischemic attack (TIA) had a favorable effect on early outcome after acute nonlacunar ischemic stroke. METHODS: Data of 1,753 consecutive patients with ischemic stroke collected from a prospective hospital-based stroke registry were studied. A comparison was made of the groups with and without previous TIA. Favorable outcome included spontaneous neurological recovery or grades 0-2 of the modified Rankin scale at hospital discharge. RESULTS: Previous TIA occurred in 55 (11.5%) of 484 patients with lacunar stroke and in 166 (13.1%) of 1,269 patients with nonlacunar stroke. The percentage of nonlacunar ischemic stroke patients with favorable outcome was 21.7% in those with a history of TIA compared to 15% without TIA (p < 0.03). In the lacunar stroke group, differences were not significant. In the multivariate analysis, TIA was an independent predictor of spontaneous in-hospital recovery. CONCLUSIONS: Prior TIA was associated with a favorable outcome in nonlacunar ischemic stroke, suggesting a neuroprotective effect of TIA possibly by inducing a phenomenon of ischemic tolerance allowing better recovery from a subsequent ischemic stroke.     

The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke

Tumor necrosis factor (TNF)-alpha overexpression has been related to experimental ischemic tolerance when transient ischemia precedes cerebral infarction. We investigated TNF-alpha and interleukin (IL)-6 plasma concentrations in 283 patients with an acute stroke within 24 hours after symptom onset. An ipsilateral transient ischemic attack (TIA) within 72 hours before stroke was recorded in 38 patients. The infarct volume measured on computed tomography on days 4 to 7 and the frequency of poor outcome (Barthel Index score < 85) at 3 months were significantly lower in patients with prior TIA. Plasma concentrations of TNF-alpha were higher (42.5 +/- 9.9 vs 13.1 +/- 6.4pg/ml, p < 0.0001) and IL-6 levels were lower (10.1 +/- 6.2 vs 28.3 +/- 17.3pg/ml, p < 0.0001) in patients with prior TIA. A new variable termed TNF-alpha/IL-6 index was considered positive when TNF-alpha was greater than 30pg/ml and IL-6 was less than 30pg/ml. Positive TNF-alpha/IL-6 index was found in 92% of patients with prior TIA and in 1% of those without. TNF-alpha/IL-6 index (p = 0.0003) and TIA (p = 0.0001) were associated with good outcome in logistic regression analysis after adjusting for potential confounding factors. Ischemic tolerance in acute stroke is associated with increased plasma levels of TNF-alpha in the presence of reduced concentrations of IL-6.     

短暂性脑缺血发作对卒中后脑保护的临床观察

目的比较短暂性脑缺血发作(TIA)后卒中与无TIA发作脑卒中患者临床预后,探讨体内缺血预适应对脑组织保护机制;方法选择首次急性脑卒中住院患者340例,按有无TIA发作分为TIA组和无TIA组,观察患者神经功能改善情况及再梗死率,并分析日常生活活动能力恢复程度;结果与无TIA发作组比较,既往有与此次脑梗死相关TIA组患者临床症状明显改善;结论 TIA作为体内缺血预适应可诱导一系列内源性保护机制减少脑组织损伤。     

Transient ischemic attack: A neurologic emergency

Classically, a transient ischemic attack (TIA) has been defined as an acute episode of neurologic symptoms lasting less than 24 hours attributed to focal ischemia in a vascular distribution of the brain or retina. Stroke and TIA share similar risk factors, evaluation, and secondary prevention. However, evaluation of patients with TIA has traditionally lacked the same urgency that has been directed to acute stroke, probably because patients with TIA are at baseline neurologically when the diagnosis is made. Recently, several studies have found a high risk of stroke shortly after TIA. Furthermore, recent evidence suggests that early recovery from ischemia actually is associated with greater instability. Identifying patients with the highest risk of recurrent ischemic events for urgent evaluation and intervention is key in secondary stroke prevention. This article reviews the current literature on new concepts about TIA, subsequent risk of stroke, and guidelines on evaluation and treatment.     

Comparison of population-based models of risk factors for TIA and ischemic stroke.

OBJECTIVE: To determine whether there is a difference in the risk factors for ischemic stroke and for TIA. BACKGROUND: TIA is associated with a high risk for ischemic stroke, but some have considered TIA as mild ischemic stroke. Prevention of disabling stroke is sufficient reason to label TIA as a precursor for stroke, but some risk factors may be more or less associated with TIA than with ischemic stroke, suggesting differences in mechanism. METHODS: The medical records linkage system for the Rochester Epidemiology Project provided the means of identifying first episodes of TIA in the Rochester, MN population among those who had not had ischemic stroke. Control subjects were selected from an enumeration of the population through the medical records. The exposure to various risk factors was ascertained. The conditional likelihood approach to estimate the parameters of a multiple logistic model permitted estimation of the OR for TIA for each risk factor while adjusting for confounding variables. RESULTS: The multivariable logistic regression model for TIA shows that the estimates of the ORs for ischemic heart disease, hypertension, persistent atrial fibrillation, diabetes mellitus, and cigarette smoking are similar to the ORs for those variables in the ischemic stroke model. However, the OR for mitral valve disease in the TIA model is 0.4, suggesting that mitral valve disease is unlikely to be associated with cerebral ischemic episodes that are brief enough to be called TIA.     

Rheumatoid arthritis significantly increased recurrence risk after ischemic stroke/transient ischemic attack

The effect of RA on recurrent stroke is unknown. Therefore, we examined effects of rheumatoid arthritis (RA) on risk of stroke recurrence and investigated the interaction between RA and traditional cardiovascular risk factors on recurrence risk after ischemic stroke (IS) or transient ischemic attack (TIA). Of 3190 patients with IS or TIA recruited in this cohort study, 638 were comorbid with RA and 2552 without RA. Stroke recurrence, RA, lifestyle, lipid variables and other comorbidities were identified through linkage between a nationwide stroke database in Taiwan and the National Health Insurance claims database. Cox proportional hazard models with competing risk adjustment were used to evaluate the relationship between RA and recurrent stroke. Patients with RA showed a significantly increased risk of recurrent stroke, particular in recurrent IS/TIA. The increased risk of recurrent IS/TIA in RA patients may through the changes of triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C) ratio. A positive additive interaction was observed between RA and current smoking on the risk of recurrent IS/TIA. Significantly increased risks for recurrent IS/TIA were observed among RA patients who smoked?>?40 years or those who smoked?>?20 cigarettes/day. This study provides the first evidence that RA significantly increased recurrence IS/TIA risk. The changes of TG/HDL-C ratio may play some roles in the recurrence IS/TIA risk in RA patients. In addition, our results suggest that smoking increases the risk of recurrent IS/TIA in RA patients and reinforces the need for aggressive smoking cessation efforts in RA patients.     

Transient ischemic attack: a dangerous Harbinger and an opportunity to intervene

Transient ischemic attack (TIA) and ischemic stroke are both characterized by sudden onset of neurological symptoms due to focal cerebral ischemia, but they are distinguished by the duration of neurological symptoms, with TIA traditionally defined by resolution of symptoms within 24 hours and stroke reserved for symptoms of longer duration. Because TIA and ischemic stroke share etiologies, it is not surprising that the recommended evaluations and secondary prophylaxis are identical. However, recent studies suggest that optimal management of TIA and stroke may differ more than previously recognized. The short-term risk of ischemic stroke after TIA is very high, which may be because rapid recovery from neurological symptoms is indicative of reversal of ischemia and tissue still at risk. Regardless of whether residual symptoms or infarction are present, rapid recovery appears to predict a greater short-term risk of subsequent ischemic stroke and is more likely to reflect a distinct, unstable pathophysiology. Therefore, it may be more useful to characterize acute ischemic cerebrovascular syndromes on the basis of the extent of rapid recovery (i.e., on the inferred reversal of ischemia) than on the completeness of recovery at 24 hours. Patients with substantial rapid recovery may be those for whom acute intervention is most warranted.     

C-reactive protein predicts further ischemic events in transient ischemic attack patients

BACKGROUND AND PURPOSE: Although patients with transient ischemic attack (TIA) experience cardiovascular events frequently, strong clinical predictors of recurrence are lacking. High-sensitivity C-reactive protein (hs-CRP) has been shown to be a powerful predictor of future first-ever and recurrent coronary and cerebral ischemic events. We aimed to investigate the relationship between hs-CRP and the risk of further ischemic events in TIA patients. METHODS: High-sensitivity C-reactive protein level was determined <24 h after symptom onset among 135 consecutive TIA patients and stroke recurrence or any new vascular event was recorded during 1 year follow-up period. RESULTS: A total of 38 (28.1%) patients experienced an end point event: 28 (20.7%) cerebral ischemic events, six (4.4%) heart ischemic events, four (3%) peripheral arterial disease, and nine (6.7%) vascular deaths. Cox proportional hazards multivariate analyses identified age [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.01-1.12, P = 0.01], large-artery occlusive disease (HR 2.73, 95% CI 1.16 to 6.41, P = 0.02) and hs-CRP> 4.1 mg/l (HR 2.81, 95% CI 1.12-7.10, P = 0.03) as independent predictors of stroke. Moreover, age (HR 1.05, 95% CI 1.01-1.10, P = 0.02), large-artery occlusive disease (HR 3.12, 95% CI 1.48-6.58, P < 0.01), coronary disease (HR 2.39, 95% CI 1.11-5.16, P = 0.03), and hs-CRP> 4.1 mg/l (HR 2.71, 95% CI 1.16-6.30, P = 0.02) were also independent predictors of any vascular event. CONCLUSIONS: High-sensitivity C-reactive protein serum level predicts further ischemic events following TIA. Routine CRP measurement might be a useful tool for identifying high-risk TIA patients in order to plan aggressive diagnostic protocols and prevention therapies.     

Diffusion MRI in patients with transient ischemic attacks.

BACKGROUND AND PURPOSE: Diffusion MRI has established value in patients with ischemic stroke but has not been systematically investigated in patients with transient ischemic attack (TIA). METHODS: Clinical, conventional MRI, and diffusion MRI data were collected on 42 consecutive patients with symptoms of cerebral TIA. TIA imaging data were compared with those from a contemporaneous group of 23 completed stroke patients. RESULTS: Twenty of the 42 TIA patients (48%) demonstrated neuroanatomically relevant focal abnormalities on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging. When present, DWI/ADC signal changes in TIA patients were less pronounced and smaller in volume than those in completed stroke patients. TIA symptom duration was significantly longer for DWI-positive than for DWI-negative patients, 7.3 versus 3.2 hours. Diffusion MRI information changed the suspected anatomic and vascular TIA localization and the suspected etiologic mechanism in over one third of patients with diffusion MRI abnormalities. Of the 20 TIA patients with identifiable lesions on diffusion MRI, 9 had follow-up imaging studies; of these, 4 did not show a relevant infarct on follow-up imaging. CONCLUSIONS: Diffusion MRI demonstrates ischemic abnormalities in nearly half of clinically defined TIA patients. The percentage of patients with a DWI lesion increases with increasing total symptom duration. In nearly half, the diffusion MRI changes may be fully reversible, while in the remainder the diffusion MRI findings herald the development of a parenchymal infarct despite transient clinical symptoms. Finally, diffusion imaging results have significant clinical utility, frequently changing the presumed localization and etiologic mechanism.     

Joint effects of risk factors for stroke and transient ischemic attack in a German population

BACKGROUND: Single, modifiable risk factors for stroke have extensively been studied. In contrast, differences of their combined effects among stroke and transitoy ischemic attack (TIA) have been rarely investigated. The aim of the present study was to assess single and joint effects of risk factors on the incidence of stroke and TIA and to compare their magnitudes in a large population-based German cohort. METHODS: Incident cases of stroke and TIA were identified among 25,538 participants (aged 35-65 at baseline) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Relative risks for stroke and TIA related to modifiable risk factors were estimated using Cox proportional hazard models. RESULTS: During 4.3 years of follow-up 100 stroke cases and 112 TIA cases occurred. Incidences of stroke and TIA were 91.7 and 102.7 per 100,000 person-years, respectively. Relative risks for ischemic stroke (RR 5.12, 95% CI 1.49-17.6, p for trend<0.0001) and for TIA (RR 3.08, 95% CI 1.00-9.44, p for trend<0.024) were highest among participants having 4 or 5 modifiable risk factors. 58.5% of ischemic strokes and 26.2% of TIA cases were attributable to the 5 risk factors hypertension, diabetes mellitus, high alcohol consumption, hyperlipidemia, and smoking. CONCLUSION: Our data indicate that classical risk factors may explain almost 60% of ischemic stroke but only one in four TIA cases. Analysing potential differences of known risk factors between ischemic stroke and TIAs and the identification of other determinants of ischemic attacks are important steps to better explain the burden of stroke.