细胞凋亡在蛛网膜下腔出血后脑血管痉挛发病中的作用

背景 脑血管痉挛(cerebral vasospasm,CVS)是蛛网膜下腔出血(subarachnoid hemorrhage,SAH)和颅内动脉瘤术后致死或致残的主要并发症之一,如何有效地治疗脑血管痉挛成为防治SAH的主要目标,但其确切机制尚不清楚,新近许多研究表明细胞凋亡可能在SAH后CVS的发病中发挥重要作用....     

Role of prostaglandins in delayed cerebral ischemia after subarachnoid hemorrhage.

Prostaglandin E2, thromboxane B2, and 6-oxo-prostaglandin F1 alpha were assayed in blood and cerebrospinal fluid samples from patients after subarachnoid hemorrhage (SAH) and from a control population. The levels found in samples obtained from patients after SAH were compared with those found in controls and were also correlated with a number of clinical and radiological variables, many of which are either significantly associated with or represent evidence of cerebral ischemia. The levels of prostaglandin E2, thromboxane B2, and 6-oxo-prostaglandin F1 alpha in blood samples from patients after SAH and from controls were below the level of sensitivity of the assays. Levels of prostaglandin E2, thromboxane B2, and 6-oxo-prostaglandin F1 alpha in cerebrospinal fluid from patients after SAH were significantly elevated when compared with those found in control samples. There was no significant correlation, however, between the level of each prostaglandin measured and the following variables: clinical grade on admission as assessed by the Glasgow Coma Score and the World Federation of Neurological Surgeons grading system; the amount of subarachnoid blood seen on computed tomographic scan; the occurrence of ischemic deterioration; the occurrence of low density change on computed tomographic scan; the presence of vasospasm on angiography; clinical outcome as assessed by the Glasgow Coma Score 3 months after the ictus; and the incidence of ischemia as a cause of death or disability as assessed 3 months after the ictus. A primary role for prostaglandins in the etiology of delayed cerebral ischemia after SAH is not therefore confirmed.     

HLA-type of cerebral vasospasm patients after aneurysmal subarachnoid hemorrhage

We studied human lymphocyte antigen (HLA) types in a group of 45 patients who had aneurysmal subarachnoid hemorrhage (SAH). A significantly increased frequency of HLA antigen A31 and a significantly decreased frequency of HLA antigen B40 were found. In patients with delayed ischemic neurological deficit (DIND) following aneurysmal SAH and HLA typing, HLA-Bw60 antigen showed significant increases; in patients who did not develop HLA-Aw33 and-Cw4 antigens showed significant. Among the patients with Fisher's Group 3 on CT, in particular, these antigens significantly increased when compared with controls from the same geographic area. These results suggest that HLA-Bw60 antigen plays a role as a predisposing factor of DIND resulting from vasospasm following aneurysmal SAH, and that HLA-Aw33 and-Cw4 exert protective influence against DIND.     

Cerebral vasospasm after subarachnoid hemorrhage

Cerebral vasospasm causes permanent neurolological deficit or death occurance in 13% of clinical cases. Peak frequency is from 8-10th day after SAH. The purpose of this study is factor analysis that may have influence on vasospasm development , as well as predictor determination. The study is prospective and analysis 192 patients treated in Institute of Neurosurgery, Clinical Centre of Serbia, Belgrade. The majority of patients were admitted in hospital in first four days after SAH, and 184 had GCS over 7. Univariate methods of factor analysis were used, and for significance of predictors influence testing multivariante regression analysis was used. Vasospasm occurred in 22,40% of all cases. No relationships have been found between sex, age, previous hypertension, timing of surgery, appearance of hydrocephalus and intracerebral hematoma, hypertermia or mean arterial blood pressure, with occurrence of cerebral vasospasm. Factors with significantly associated with the occurance of vasospasm were: hearth disease, hypernatriemia, Hct, clinical grade on admission as well as preoperative clinical grade and Fisher CT scan grade. In the first four days after SAH, Fisher scan grade, preoperative clinical grade and Hct, appeared as predictors. After four days, clinical grade on admission and hypernatiemia, showed as poredictors.     

Procedural predictors of delayed cerebral infarction after intra-arterial vasodilator infusion for vasospasm following aneurysmal subarachnoid hemorrhage

Purpose  

The goals of this study were to identify predictors of delayed cerebral infarction in aneurysmal SAH after intra-arterial (IA) vasodilator infusion and to select proper parameters for treatment success.     

辛伐他汀对蛛网膜下腔出血后迟发性脑血管痉挛的影响及作用机制

目的本研究拟观察辛伐他汀对蛛网膜下腔出血后迟发性脑血管痉挛的影响，并探讨其机制。方法随机将新西兰白兔36只均分为假手术组、自发性蛛网膜下腔出血（SAH）组和SAH＋辛伐他汀组（n=12）。假注血组动物行枕大池假穿刺假注血，其他2组受试动物行枕大池穿刺2次注血的方法，制作迟发性脑血管痉挛模型。于0～6d。经口给予SAH＋辛伐他汀组家兔辛伐他汀5mg／kg体重，其他动物给予等量的淀粉。所有受试动物在第1次穿刺后的第7天被处死，比较不同组间基底动脉内径、内径与血管壁厚度之比（D／T）的变化；并应用免疫组织化学、逆转录．聚合酶链反应（RT-PCR）的方法对家兔基底动脉的肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和IL-6表达进行评价。结果与SAH组比较。SAH＋辛伐他汀组动物血管痉挛明显缓解（P〈0．05）、其血管壁促炎细胞因子TNF-α、IL-1β和IL-6表达显著减少（P〈0．05）。结论经口给予一定量的辛伐他汀（5mg／kg体重）能明显缓解蛛网膜下腔出血后迟发性脑血管痉挛，其作用机制可能与辛伐他汀的抗炎作用有关。     

Effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage in rats

The effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage (SAH) was investigated in a rat model. Seven groups of seven rats underwent no SAH, no treatment; SAH only; SAH plus vehicle; SAH plus 3 days intraperitoneal raloxifene treatment; SAH plus 4 days intraperitoneal raloxifene treatment; SAH plus 3 days intrathecal raloxifene treatment; and SAH plus 4 days intrathecal raloxifene treatment. The basilar artery cross-sectional areas were measured at 72 or 96 hours following SAH. The results showed raloxifene decreased SAH-induced cerebral vasospasm in all treatment groups, and suggested no difference between intraperitoneal and intrathecal application, or between 3 days and 4 days of raloxifene treatment. The present study demonstrates that raloxifene is a potential therapeutic agent against cerebral vasospasm after SAH.     

Contribution of Src tyrosine kinase to cerebral vasospasm after subarachnoid hemorrhage

OBJECT: Mitogen-activated protein kinase (MAPK) has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether Src tyrosine kinase, an upstream regulator of MAPK, is involved in cerebral vasospasm. METHODS: An established canine double-hemorrhage model was used. Twenty-four dogs were divided into four groups: control, vehicle-treated, Src inhibitor PP2-treated, and Src inhibitor damnacanthal-treated groups. Vehicle (dimethyl sulfoxide), PP2, or damnacanthal was injected daily into the cisterna magna of 18 dogs at 3 to 6 days after induction of SAH. Angiography was performed on Day 0 (the day on which the first blood injection was administered to induce SAH) and on Day 7. Western blot analysis of Src and MAPK activation in basilar arteries (BAs) collected on Day 7 post-SAH was performed. Severe vasospasm was observed in the BAs of vehicle-treated dogs. Mild vasospasm was observed in all dogs treated with Src inhibitors. Phosphorylated Src and MAPK were increased after SAH and activation of these kinases in the BAs was abolished by PP2 and damnacanthal. CONCLUSIONS: The tyrosine kinase Src is an important upstream regulator of MAPK, and inhibition of Src might offer a new therapy in the management of cerebral vasospasm.     

Effects of raloxifene on cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits

Background

The aim of this study was to investigate the ability of a SERM, RLX, to prevent vasospasm in a rabbit model of SAH.

Methods

Thirty-four New Zealand white rabbits were allocated into 3 groups randomly. Subarachnoid hemorrhage was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: (1) sham operated (no SAH [n = 12]), (2) SAH only (n = 12), and (3) SAH plus RLX (n = 10). Basilar artery lumen areas and arterial wall thickness were measured to assess vasospams in all groups.

Results

There was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (P < .05). The difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements in the RLX-treated group was statistically significant (P < .05). The difference between the SAH group and the SAH + RLX group was also statistically significant (P < .05).

Conclusions

These findings demonstrate that RLX has marked vasodilatatory effect in an experimental model of SAH in rabbits. This observation may have clinical implications suggesting that this SERM drug could be used as possible anti-vasospastic agent in patients without major adverse effects.     

N-acetylcysteine prevents vasospasm after subarachnoid hemorrhage

BackgroundThis study investigated the ability of NAC to prevent cerebral vasospasm in a rabbit model of SAH.MethodsTwenty-one, male New Zealand white rabbits were randomly divided into 3 groups of 7 rabbits each: group 1 (control), group 2 (SAH only), group 3 (SAH + NAC treatment). NAC (150 mg/kg, single dose, IP) was administered just before SAH and continued until 72 hours after SAH in group 3.Animals were killed 72 hours after SAH. Tissue MDA levels, SOD, and GSH-Px activities were measured, and basilar artery cross-sectional areas, arterial wall thickness, and endothelial apoptosis in a cross section of basillary artery were determined in all groups.ResultsIntraperitoneal administration of NAC was found to be markedly effective against developing a cerebral vasospasm following a SAH in rabbits. It could significantly reduce elevated lipid peroxidation and increase the level of tissue GSH-Px and SOD enzymatic activities. Also, NAC treatment was found to be effective in increasing the luminal area and reducing wall thickness of the basilar artery. The morphology of arteries in the NAC treatment group was well protected. NAC markedly reduced apoptotic index and protects the endothelial integrity.ConclusionsThis study demonstrates, for the first time, that NAC treatment attenuates cerebral vasospasm in a rabbit SAH model. NAC treatment has significant neuroprotective effect and markedly prevents cerebral vasospasm after SAH. In conclusion, the NAC treatment might be beneficial in preventing cerebral vasospasm after SAH, thus showing potential for clinical implications.     

Monitoring jugular venous oxygen saturation in severe cerebral vasospasm after subarachnoid hemorrhage

Cerebral arterial vasospasm is a major complication of aneurysmal subarachnoid haemorrhage. The conventional treatment of this complication includes haemodilution, hypervolaemia, arterial hypertension and nimodipine. Some patients do not respond to this therapy and require an intraarterial infusion of papaverine and/or a cerebral angioplasty. Transcranial Doppler detects cerebral vasospasm. However it does not provide an accurate metabolic information on the ischaemic status of the cerebral tissue. This article describes the monitoring of jugular venous bulb oxygen saturation to obtain a real time information on the metabolic effect of cerebral vasospasm and its variations after intra-arterial infusion of papaverine.     

Role of computed tomography in the management of vasospasm after subarachnoid hemorrhage

The role of computed tomography (CT) in the management of vasospasm from subarachnoid hemorrhage was evaluated in 242 consecutive cases with CT performed within 7 days after hemorrhage. Only 20% of these cases did not show a detectable subarachnoid hemorrhage on CT. Subsequent angiograms showed vessel narrowing in 56% of the cases; associated clinical deterioration was noted in 34% of the cases. On later CT, clear ischemic areas were detected in 20% of the cases. A strict correlation between the amount of cisternal blood and the subsequent development of vasospasm was observed: although absent or thin cisternal depositions were rarely associated with vasospasm, consistent or thick depositions were frequently linked to vasospasm (72% of the cases) and to ischemic disturbances (51% of the cases), as well as to clear ischemic areas on later CT (30% of the cases). Regarding the morphology of the cisternal blood collection, the risk of developing vasospasm was at its lowest (42%) for depositions only in the frontal interhemispheric fissure and was at its highest (79%) for depositions in multiple cisterns. The site of cisternal deposition corresponded closely to the area of ischemia on later CT. The persistence of subarachnoid blood more than 72 hours after hemorrhage probably increases the risk of vasospasm, although our data are not conclusive. The definition of a CT scan "at risk" for vasospasm--based on the previous findings--gives practical advantages: proper selection of patients in regard to timing of operation, closer observation and the possibility of prophylactic treatment in patients "at risk," and more adequate evaluation of different therapeutic modalities for vasospasm. With regard to the last point, the incidence of vasospasm was not statistically different between two groups of patients uniformly "at risk": the first group submitted to early operation and the second awaiting operation.     

蛛网膜下腔出血后脑血管痉挛的研究进展

脑血管痉挛(cerebral vasospasm,CVS)是蛛网膜下腔出血(subaraachnoid hemorrhage,SAH)后一种常见的灾难性的并发症,其所致迟发性缺血性神经功能损害是造成患者致残和死亡的最主要原因.虽经多年研究,但其发病机制至今尚未完全阐明.一氧化氮、内皮素-1、血红蛋白氧化产物及炎症反应均被认为参与致病过程.针对这些发病机制的治疗措施目前仍处于研究阶段,预期会在今后的脑血管痉挛的防治中发挥重要作用.     

Role of ERK1/2 and vascular cell proliferation in cerebral vasospasm after experimental subarachnoid hemorrhage

Background  

Although there are still some unresolved aspects, current research has revealed that vascular cell proliferation probably plays an important part in the pathological formation process of cerebral vasospasm. Using a “two-hemorrhage” model of subarachnoid hemorrhage (SAH), this study investigated the function of ERK1/2 and vascular wall cell proliferation in pathological development of cerebral vasospasm.     

Role of bedside microdialysis in the diagnosis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage

OBJECT: Ischemia due to vasospasm is a feared complication in patients following aneurysmal subarachnoid hemorrhage (SAH). Cerebral online microdialysis monitoring may detect the metabolic changes in the extracellular fluid associated with ischemia. The aims of the present study were to correlate clinical course, microdialysis-recorded data, transcranial Doppler (TCD) ultrasonography findings, and angiographic findings in patients with SAH. METHODS: In 60 patients a microdialysis catheter was inserted into the brain parenchyma that is most likely to be affected by vasospasm directly after aneurysm clipping. Hourly analyses of glucose, pyruvate, lactate, and glutamate levels were performed using a bedside device. Blood-flow velocities were obtained using serial TCD measurements. Cerebral angiography was routinely performed on Day 7 after aneurysm clipping or earlier in cases of clinical deterioration (30 patients). In all patients the results of microdialysis monitoring, TCD ultrasonography, and angiography were correlated. The mean duration of monitoring was 7.3+/-2.5 days. In patients with acute ischemic neurological deficits (18 patients) immediate microdialysis-recorded alterations were observed if the probe was placed close to the malperfused region. In 13 of 15 patients with symptomatic vasospasm (delayed ischemic neurological deficit [DIND]), the microdialysis-recorded values revealed secondary deterioration. In terms of confirming DIND, microdialysis had the highest specificity (0.89, 95% confidence interval [CI] 0.78-1) compared with TCD ultrasonography (0.63, 95% CI 0.46-0.8) and angiography (0.53, 95% CI 0.35-0.7). For microdialysis, the positive likelihood ratio was 7.8, whereas this was significantly lower for TCD ultrasonography (1.7) and angiography (2.1). CONCLUSIONS: Although angiography also demonstrates vessel narrowing in asymptomatic patients, online microdialysis reveals characteristic metabolic changes that occur during vasospasm. Thus, online microdialysis may be used to confirm the diagnosis of vasospasm.     

蛛网膜下腔出血后脑血管痉挛的影像学和免疫组织化学研究

目的　应用脑血管造影 (DSA)和免疫组织化学方法探讨二次注血复制CVS模型效果和内皮素转化酶ECE抑制剂 [D Val2 2 ]大ET 1(16 3 8)对内皮素 (ET 1)表达的影响。方法　采用枕大池 2次血法制备兔SAH后CVS模型 ,将 3 6只白兔随机分成生理盐水对照组、SAH组、脑池给药预防组、静脉给药预防组、脑池给药治疗组和静脉给药治疗组。全部白兔于首次注血前后 7d分别进行脑血管造影 ,测量基底动脉直径 ;7d后取基底动脉进行免疫组织化学染色。结果　注血模型均能形成CVS ;SAH组实验前基底动脉直径 (0 .7± 0 .0 79)mm ,7d后直径为 (0 .47± 0 .0 75 )mm (P <0 .0 5 )。ET 1免疫阳性标记颗粒在各组中间均有不同程度的表达 ,以SAH组最重。结论　 2次注血模型能够很好模仿人类蛛网膜下腔出血 ;[D Val2 2 ]大ET 1(16 3 8)可明显抑制SAH后基底动脉壁ET 1的免疫表达。