局部选择性脑部低温联合颈动脉灌注硫酸镁治疗急性局灶性脑缺血的实验研究
|
摘要
目的
建立大鼠颈内动脉冷生理盐水灌注选择性脑部低温模型,探讨冷生理盐水灌注对大鼠生理指标以及局部脑组织的影响,评价本选择性脑部降温方案的安全性。采用经过激光多普勒筛选的大鼠3h大脑中动脉闭塞(middle cerebral artery occlusion, MCAO)模型,探讨颈内动脉冷生理盐水灌注对梗死体积、脑水肿、急性期神经功能预后的影响,评价选择性脑部低温对急性局灶性脑缺血的治疗作用。
采用经激光多普勒筛选的大鼠MCAO模型,予颈内动脉灌注不同剂量的硫酸镁,探讨硫酸镁对梗死体积、神经功能预后、脑含水量的影响,评价颈内动脉灌注硫酸镁对急性局灶性脑缺血的治疗效果,并确定局部灌注硫酸镁的最佳治疗剂量。
利用激光多普勒筛选的大鼠MCAO模型,在局灶性脑缺血后3h予局部灌注治疗,探讨选择性脑部低温联合颈内动脉灌注硫酸镁对梗死体积、急性期神经功能预后、脑含水量、脑组织伊文思蓝含量、血清MMP-9浓度的影响。在缺血3h再灌注后不同的时间给予治疗,探讨联合方案对选择性脑部低温治疗脑缺血时间窗的影响。
方法
采用随机设计,将58只SPF级雄性Sprgue-Dawley大鼠随机分至以下六组：假手术组(n=5),正常大鼠灌注组(n=5),梗死组(n=12),局部低温组(n=12),局部常温组(n=12),静脉低温组(n=12)。正常灌注组以及局部低温组大鼠采用颈内动脉置管,以0.4m1/min速度灌注15℃生理盐水持续20min,记录灌注前后的脑温、肛温,探索选择性低温治疗对脑温、肛温的影响以及两者之间的关系。比较选择性低温过程中心率、平均动脉压、红细胞压积、钠离子浓度、氯离子浓度、钾离子浓度、血糖以及血气指标的变化,分析脑温变化与各指标的关系。观察灌注后脑组织的形态改变以及测量灌注后脑含水量情况。制作大鼠MCAO模型,应用激光多普勒筛选入组动物,入选的造模动物根据分组予以不同的灌注方案,比较各组各时间点生理指标的差异。术后48h各组脑组织行TTC染色以及脑含水量测定,比较各组相对梗死体积以及脑含水量之间的差异。术后24h以及48h行mNSS评分评价各组缺血后神经功能损害程度,比较各组间以及各组内两个时间评分的差异。
采用随机设计,78只大鼠随机分入以下各组：假手术组(n=6)、梗死组(n=12)、生理盐水组(n=12)、硫酸镁A组(n=12)、硫酸镁B(n=12)、硫酸镁C组(n=12)、硫酸镁D组(n=12)。硫酸镁灌注组根据分组分别给予四个治疗剂量的硫酸镁(60mg/kg,90mg/kg,120mg/kg,150mg/kg)。制作大鼠MCAO模型,应用激光多普勒筛选入组动物,入选的造模动物根据分组予以不同的灌注治疗方案。硫酸镁灌注组大鼠在MCAO缺血2h再灌注同时以0.4ml/min速度灌注37℃硫酸镁(不同剂量)持续20min。生理盐水灌注组大鼠在MCAO缺血2h以后以同样的速度灌注37℃生理盐水持续20min。比较各组术前、灌注前、灌注后的心率、平均动脉压、血气分析指标、红细胞压积以及血糖水平。比较各组术前、术后、再灌注60min、再灌注120min、再灌注24h以及再灌注48h的肛温水平。在术后48h处死动物取脑切片行TTC染色,比较各组动物的相对梗死体积。取脑用干湿重法测量脑含水量,比较各组缺血后的脑组织含水量。在术后24h、48h进行神经功能检查,比较各组之间以及各组不同检查时间点之间的mNSS评分。
采用随机设计,152只动物被随机分成6组：假手术组(n=8)、梗死组(n=16)、常温盐水组(n=16)、常温镁组(n=16)、低温盐水组(n=48)、低温镁组(n=48),低温盐水组及低温镁组根据不同的低温灌注治疗时间(再灌注立即、再灌注后1h、再灌注后2h)再分为三个亚组。各组制作MCAO模型,应用激光多普勒筛选入组动物。入选的动物在缺血后予以不同的灌注方案,比较各组各时间点生理指标的差异,术后48h行TTC染色,称量脑组织干湿重,比较各组的相对梗死体积以及脑含水量。采用酶标仪测定脑组织伊文思蓝含量,采用Elisa法测量血清MMP-9浓度,比较各组之间的差异。
结果
冷生理盐水灌注前后各个时间点之间的脑温有显著差异(F=2035.541,P<0.001)。肛温在灌注过程略微下降,但灌注前后不同时间点肛温的差异无统计学意义(F=1.448,P>0.05)。从各个时间点看,灌注前脑温与肛温无显著差异(P>0.05),但低温灌注开始后脑温始终显著低于肛温(P<0.05)。低温灌注前后以及不同部位之间存在交互效应(F=1100.437,P<0.001)。在颈内动脉冷生理盐水灌注过程中脑温与肛温无相关性(r=0.169,P=0.078)。灌注前后各个时间点心率、平均动脉压、血气分析指标、红细胞压积、血糖、血钠、血氯以及血钾均无显著差异(均P>0.05),灌注过程脑温与各指标之间均无相关关系(均P>0.05)。正常灌注组48h后大脑TTC染色以及HE染色均无明显异常,脑含水量与假手术组无显著差异,48h mNSS评分0分。各组MCAO入选的大鼠基线资料均衡(均P>0.05)。灌注前后不同观察时间点之间脑温有显著的差异(F=386.698,P=0.000),不同组别之间的脑温存在显著差异(F=5480.737,P=0.000),且不同组别的脑温在不同的观察时间点变化的趋势不同(F=334.817,P=0.000)。从各个观察时间点看,在灌注前各个实验组脑温无显著差异(P>0.05),从灌注开始5min时局部低温组的脑温显著低于其他组别(P<0.001),在灌注持续20min时脑温降至最低水平,停止灌注后脑温逐渐回升,在80min时脑温与其他组别脑温无显著差异(P>0.05)。各个组别之间的肛温无显著差异(P>0.05)。各组之间梗死体积的差异具有统计学意义(F=124.402,P<0.001),局部低温组的梗死体积显著低于其余各组(均P<0.05)。各组间24h与48h mNSS评分差异有统计学意义。(F值分别为9.296,10.303,均P=0.000),局部低温组mNSS评分显著低于其它各组(均P<0.05),局部低温组24h与48h mNSS评分之间有显著差异(P<0.05)。各组脑含水量的差异有统计学意义(F=24.087,P=0.000),梗死组及各治疗组的脑含水量均显著高于假手术组(P>0.05),局部低温组的脑含水量显著低于梗死组(P<0.05)。
重复测量方差分析的结果表明,不同时间点的心率无显著差异(F=1.118,P=0.334),不同组别心率有显著差异(F=5.003,P=0.002),不同组别的心率随着不同时间点的变化趋势不同(F=4.053,P=0.000)。从各时间点看,灌注后各组的心率差异有统计学意义(F=9.588,P=0.000),且硫酸镁D组的心率显著低于其他各组的心率水平(均P<0.05)。不同时间点与不同组别的平均动脉压无显著差异(F值分别为1.555与1.613,P值分别为0.220,0.187),平均动脉压在不同的组别不同观察时间变化的趋势不同(F=2.287,P=0.024)。从各个时间点看,灌注后各个组间的平均动脉压存在显著差异(F=4.533,P=0.003),硫酸镁D组的平均动脉压显著低于梗死组、生理盐水组、硫酸镁A组与B组(均P<0.05)。血气指标、红细胞压积、血糖水平在不同时间点、不同组别间的差异均无统计学意义。术前及术后不同阶段的肛温值有显著差异(F=3.259,P=0.008),不同组别肛温无显著差异(F=2.345,P=0.065)。在各个检查时间点内,各组别肛温的差异无统计学意义(均P>0.05)。不同组别的梗死体积有显著差异(F=53.723,P=0.000)。硫酸镁C组的梗死体积最小。所有治疗组的梗死体积均显著小于梗死组(均P<0.05),所有硫酸镁治疗组的梗死体积均显著小于生理盐水组(均P<0.05),硫酸镁C组的梗死体积显著小于梗死组、生理盐水组、硫酸镁A组及硫酸镁B组(均P<0.05)。硫酸镁C组梗死体积与硫酸镁D组无显著差异(P>0.05)。各组间24h以及48h mNSS评分均有显著差异(F值分别为3.014与6.984,P值分别为0.025,0.000)。硫酸镁C组在两个时间段的mNSS评分均最低,硫酸镁C组24h mNSS显著低于梗死组(P<0.05),48h mNSS评分显著低于梗死组、生理盐水组以及硫酸镁A组(均P<0.05)。硫酸镁A组、硫酸镁C组、硫酸镁D组内48h mNSS均显著低于24h mNSS。各组别间脑含水量具有显著差异(F=12.518,P=0.000),梗死组及各治疗组的脑含水量均显著高于假手术组(均P<0.05),硫酸镁C组的脑含水量显著低于梗死组(P<0.05)。
各组之间的基线资料均衡(均P>0.05)。灌注前后不同时间之间脑温有显著差异(F=1271.447,P=0.000),不同组别之间的脑温有显著差异(F=4536.260,P=0.000),不同时间以及不同组别之间存在交互效应(F=447.427,P=0.000)。从各个时间看,灌注前各组脑温无显著差异(P>0.05),从灌注5min开始各组脑温存在显著差异(P<0.05),直至80min(停止灌注60min)时各组脑温差异无统计学意义(P>0.05)。在5min至65min间各个时间点内,低温盐水组与低温镁组的脑温均与梗死组有显著差异(P<0.05)。低温盐水组与低温镁组各个时间点的脑温均无显著差异(P>0.05)。各组之间的梗死体积有显著差异(F=48.007,P=0.000),低温镁组的梗死体积最小,低温盐水组与低温镁组梗死体积均显著小于梗死组(均P<0.05),低温镁组与低温盐水组梗死体积有显著差异(P<0.05)。各实验组24h与48h mNSS均有显著差异(F值分别为11.827,17.500,P值均为0.000)。低温镁组48h mNSS评分显著低于其他各治疗组(P<0.05)。各组脑含水量有显著差异(F=9.438,P=0.000),低温镁组的脑含水量显著低于梗死组(P<0.05)。各组脑组织伊文思蓝含量有显著差异(F=19.263,P=0.000),低温镁组的伊文思蓝含量显著低于梗死组(P<0.05)。各组间血清MMP-9含量有显著差异(F=4.740,P=0.004),低温镁组的MMP-9含量显著低于梗死组(P<0.05)。在各个治疗时间点内不同组别的梗死体积均有显著差异,F值分别为69.682,51.564,24.107,P值均为0.000。在再灌注即时以及再灌注后1h治疗,低温盐水组与低温镁组梗死体积均显著小于梗死组。(均P<0.05)。在再灌注2h治疗,仅低温镁组较梗死组显著降低梗死体积(P<0.05)。各个治疗时间点内不同组别的48h mNSS评分均有显著差异,F值分别为25.451,11.172,5.572,P值为0.000,0.000,0.011。在再灌注即时治疗,低温盐水与低温镁组mNSS评分均显著低于梗死组。在再灌注1h及2h治疗,仅低温镁组mNSS评分与梗死组有统计学差异(P<0.05)。各个治疗时间低温镁组的mNSS评分均显著低于低温盐水组(P<0.05)。在各个治疗时间点内不同组别的脑含水量均有显著差异,F值分别为17.063,26.766,28.507,P值均为0.000。在再灌注0h与1h时给予治疗,低温镁组脑含水量与梗死组有显著差异(P<0.05)。在再灌注后2h给予治疗,低温镁组脑含水量与梗死组差异无统计学意义(均P>0.05)。
结论
1.颈内动脉冷生理盐水灌注能够快速地降低脑温,并可以维持全身体温的恒定。
2.颈内动脉灌注冷生理盐水对局部脑组织无损害作用,并保持心率、平均动脉压、血气指标、红细胞压积、血糖以及电解质的稳定,该选择性脑部降温方法是安全的。
3.选择性脑部低温可以显著减少局灶性脑缺血后梗死体积并促进神经功能的恢复。
4.局灶性脑缺血后48h会出现不同程度的脑水肿,颈内动脉灌注冷生理盐水可有效减少脑水肿程度。
5.脑缺血后予颈内动脉灌注硫酸镁治疗可以显著减少缺血后脑梗死体积。
6.颈内动脉灌注硫酸镁可以减少24h和48h的mNSS,有利于MCAO术后的神经功能恢复。
7.脑缺血48h后出现明显脑水肿,而缺血后颈内动脉灌注硫酸镁可以明显减轻脑水肿程度,
8.颈内动脉灌注硫酸镁对脑缺血的治疗作用在60mg/kg-120mg/kg剂量之间呈剂量依赖性的,局部用药的最佳剂量是120mg/kg。
9.在对急性局灶性脑缺血治疗中,血管内选择性脑部低温联合颈内动脉灌注硫酸镁可显著减少脑梗死体积,在急性期起到脑保护作用,疗效优于各单独治疗。
10.血管内选择性低温联合颈内动脉灌注硫酸镁可显著改善24h和48hmNSS结果,有利于脑缺血后神经功能恢复。
11.联合治疗可以显著减少缺血再灌注后血清MMP-9浓度、脑组织EB含量以及脑含水量,有效保护血脑屏障,抑制血管源性脑水肿。
12.联用颈内动脉灌注硫酸镁可以延长血管内选择性脑部低温治疗急性局灶性脑缺血的时间窗。
Objective
To establish a selective brain hypothermia model induced by intra-carotid infusion of cold saline in rats and evaluate its safety on local brain tissue and physiological variables. To explore the effect of selective brain hypothermia on brain infarct volume, neurological functional outcomes and brain water content after brain ischemia.
This study was performed to determine the neuroprotective potentials of intra-carotid magnesium sulfate infusion to ischemic stroke and find the optimal protective dose of magnesium sulfate for local infusion using the filament model of transient MCAO in rats.
The aim of the study was to evaluate the protective effect of combination therapy with selective brain hypothermia and intra-carotid magnesium sulfate and determine whether intra-carotid infusion of cold magnesium sulfate would provide better neuroprotection against cerebral ischemia injury than cold saline infusion alone.
Methods
Fifty-eight male rats were randomly assigned into following groups:sham operated group (n=5), normal infusion group (n=5), stroke group (n=12), local hypothermic group (n=12), local normothermic group (n=12), systemic infusion group (n=12). Rats in normal infusion group and local hypothermic group received intra-carotid infusion of cold saline at the rate of0.4ml/min for20min. Both of brain and rectal temperature were monitored before, during and after cold infusion until the brain temperature returned to normal. Physiological variables including heart rate, mean arterial pressure, heamatocrit and blood gases were measured too. Brain sections were stained with HE and TTC to observe the morphological changes of brain tissue. Brain water content and neurological deficits were also evaluated. Rats with focal cerebral ischemia were given various infusions treatments following3h ischemia according to different groups. Physiological variables at different time point were compared among experimental groups. Brain infarct volume and cerebral water content were analyzed48h after MCAO. Neurological deficits were assessed using the mNSS24and48h after MCAO.
Seventy-eight rats were randomly divided into following groups:sham operated group (n=6), stroke group (n=12), saline group (n=12), magnesium sulfate group A (n=12), magnesium sulfate group B (n=12), magnesium sulfate group C (n=12), and magnesium sulfate group D (n=12). There were four dose of magnesium sulfate (60mg/kg,90mg/kg,120mg/kg,150mg/kg) were used in the study. Each animals in local infusion groups was given an intra-carotid magnesium sulfate or saline infusion overe a period of20min at the initiation of reperfusion (180-200min after onset of ischemia). Before reperfusion was established,8ml of magnesium sulfate or saline was injected slowly and continuously via a catheter, using an infusion pump to control the infusion rate at0.4ml/min. Physiological variables including heart rate, mean arterial pressure, blood gases, glucose and hemotocrit were measured before MCAO, before and after reperfusion. Rectal temperatures were continuously monitored until48h after MCAO. Infarct volume and brain water content were measured48h after MCAO. Neurological examinations were performed24h and48h after MCAO using the mNSS.
One hundred and fifty-two male rats were randomly assigned into following groups:sham operated group (n=8), stroke group (n=16), normothermic saline group (n=16), normothermic magnesium group (n=16), hypothermic saline group (n=48) and hypothermic magnesium group (n=48). Animals in hypothermic saline group and hypothermic magnesium group divided into three subgroups according to different initiation time of cold infusion. Each animal in local infusion groups was given an intra-carotid magnesium sulfate (15℃or37℃) or saline (15℃or37℃) infusion over a period of20min starting at the initiation of reperfusion (180-200min after onset of ischemia). Before reperfusion was established,8ml of magnesium sulfate (15℃or37℃) or saline (15℃or37℃) was injected slowly and continuously via a catheter, using an infusion pump to control the infusion rate at0.4ml/min for20min. Infarct volume and brain water contents were measured48h after MCAO. In a blinded manner, animals were examined for neurological deficit48h after MCAO using the mNSS. Evans blue (EB) concentrations in brain tissue were measured48h after MCAO. Concentrations of serum MMP-9were also measured48h after MCAO using Elisa.
Results
Significant differences were found in brain temperatures among different time points (F=2035.541, P<0.001). There was no significant difference in rectal temperatures among different time points (F=1.448, P>0.05). At each time point after cold infusion, brain temperature was significantly lower than rectal temperature (P>0.05). There was no correlation between brain temperature and rectal temperature during the monitoring periods (r=0.220, P=0.152). Physiological variables including heart rate, mean arterial pressure, blood gases, glucose and hemocrit were not significantly different among each time point. Moreover, there were no correlation between brain temperature and all physiological variables. No significant morphological abnormal was found in brain sections stained with TTC and HE. Animals received local cold infusion did not show neurological deficits48h after infusion. All baseline data was balanced between different groups (all P>0.05). Brain temperatures were significantly different before and after local infusion among groups (F values were386.698and5480.737, both P=0.000). In the local hypothermic group, brain temperature was reduced to33-34℃within5-10min and significantly lower than that in other groups after5min of commencing infusion, and this significantly low temperature was maintained to nearly60min after infusion continued. There was no significant difference in rectal temperatures among groups. A significant difference was found in infarct volume among groups (F=124.402, P<0.001). Animals treated with local cold infusion had a significantly smaller infarct volume compared with other groups (P<0.05). Both of24h and48h mNSS were significantly different among all groups (F values were9.296and10.303, all P=0.000). Both24h and48h mNSS in local hypothermic group was significantly lower than that in other groups. There was a significant difference between24h and48h mNSS in local hypothermic group. Brain water contents were significantly different among all goups (F=24.087, P=0.000). Local hypothermic group siginificantly decreased brain water contents compared to stroke group (P<0.05).
Heart rate of the animals differ significantly during the period of experiment among six study groups (F=6.185, P=0.000). After reperfusion, a significant difference was found in heart rate among study groups (F=9.588, P=0.000).Heart rate in magnesium sulfate group D decreased significantly as compared to other groups (all P<0.05). Mean arterial pressure did not significantly different during the monitored period among the study group (F value was1.555and1.613, P was0.220and0.187). After reperfusion, there was a significant difference in mean arterial pressure among groups (F=4.533, P=0.003). Mean arterial pressure in magnesium sulfate group D was significantly lower than that in stroke group, saline group, magnesium sulfate group A and B (all P<0.05). Although a significant difference in rectal temperatures was found during the monitoring period, there was no significant difference between the experimental group at each time point. The other physiological parameters of the animals were kept within normal physiological limits during the course of experiments and did not differ significantly among the study groups. There was a significant difference in infarct volume among all groups (F=53.723, P=0.000). Magnesium sulfate group C revealed the smallest infarct volume. Infarct volume in all treatment groups were significantly smaller than that in stroke group (all P<0.05). Animals treated with intra-carotid magnesium sulfate revealed decrease infarct volume compared with saline infusion (all P<0.05). Infarct volume in magnesium sulfate group C significantly smaller than that in stroke group, saline group, magnesium sulfate group A and B (all P<0.05). There was no significant difference between magnesium sulfate group C and D (P>0.05). There was a significant difference in24h and48h mNSS among all groups (F value was3.014and6.984, P was0.025and0.000). Magnesium sulfate group C revealed the least mNSS in24h and48h after MCAO. At24h after MCAO, mNSS in magnesium sulfate group C significantly less than that in stroke group (all P<0.05). At48h after MCAO, magnesium sulfate group C significantly less than stroke group, saline group and magnesium sulfate group A (all P<0.05). There was a significant difference in cerebral water contents among all groups (F=12.518, P=0.000). Brain water contents in stroke groups were significantly higher than that in sham-operated group (all P<0.05). Magnesium sulfate group C demonstrated significantly reduced brain edema compared to the stroke group (P<0.05).
Baseline data among groups were balanced (all P>0.05). Brain temperatures were significantly different during the monitoring periods among all the groups (F=447.427, P=0.000). At five minutes after local infusion, brain temperatures in cold infusion groups significantly lower than that in stroke group, this significantly low temperature maintained until60min after stopping of infusion. Brain temperatures did not differ significantly between two cold infusion groups at any time point. There was a significantly difference in infarct volume among all groups (F=48.007, P=0.000). Animals in hypothermic magnesium sulfate group revealed the least infarct volume. Infarct volume in hypothermic magnesium sulfate group was significantly smaller than that in stroke group and hypothermic saline group (P<0.05). There was a significant difference in neurological function among groups at24h and48h after MCAO (F value was11.827and17.500, all P=0.000). Rats in hypothermic magnesium group had a significantly less mNSS than other groups at48h after MCAO (P<0.05). Brain water contents were significantly different among all groups (F=9.438, P=0.000). Hypothermic magnesium group significantly decreased brain water contents compared to stroke group. Concentrations of EB was significantly different among groups (F=19.263, P=0.000). Rats in hypothermic magnesium group demonstrated less EB concentrations than stroke group (P<0.05). Serum MMP-9concentration were significantly different among groups (F=4.740, P=0.004). Serum MMP-9in hypothermic magnesium group was less than that in stroke group (P<0.05). At each treatment time point, there was a significant difference in infarct volume among all group (F value was69.682,51.564,24.107, all P=0.000). Both hypothermic saline and hypothermic magnesium significantly decreased infarct volume compared to stroke group when local infusion begined with reperfusion or1h after reperfusion (all P<0.05). At2h after reperfusion, only hypothermic magnesium group significantly reduced infarct volume compared to stroke group (P<0.05). At each treatment time point, neurological functions were significantly different among all groups at48h after MCAO (F value was25.451,11.172,5.572, P value was0.000,0.000,0.011). Both hypothermic saline group and hypothermic magnesium group significantly improved neurological outcome compared to stroke group when local infusion commenced at the beginning of reperfusion (P<0.05). Only animals treated with cold magnesium can significantly reduced mNSS compared with stroke group when treatments begin with1h and2h after reperfusion (P<0.05). A significant difference was found in brain water contents among groups at each treatment time point (F value was17.063,26.766,28.507, P=0.000). Brain water content in hypothermic magnesium group was significantly less than that in stroke group when local infusions given at reperfusion and1h after reperfusion (P<0.05). There was no significant difference in brain water content between stroke group and hypothermic groups when treatments delayed to2h after MCAO.
Conclusion
1. Selective brain hypothermia induced by intra-carotid cold saline infusion can quickly and effectively reduce the brain temperature, while maintain the rectal temperature within normal range.
2. Intra-carotid cold saline infusion did not have a harm effect on brain tissue and did not affect physiological variables. Intra-carotid infusion of cold saline is a relatively safe cooling method.
3. Intra-carotid cold saline infusion significantly reduced brain infarct volume and improved neurological functional outcomes after brain ischemia.
4. Brain water content in all stroke groups was significantly higher than that in sham-operated group48h after MCAO. Intra-carotid cold saline infusion can effectively reduce the cerebral edema after brain ischemia.
5. Intra-carotid magnesium sulfate infusion can effectively reduce infarct volume following acute focal cerebral ischemia.
6. Intra-carotid infusion of magnesium sulfate improved short-term functional outcomes after middle cerebral artery occlusion.
7. Intra-carotid magnesium sulfate infusion reduced cerebral edema48h after ischemic stroke.
8. Neuroprotective effect of magnesium sulfate in the dose of60mg/kg-120mg/kg was dose-dependent in cerebral ischemia. The optimal protective dose was120mg/kg.
9. Selective endovascular hypothermia combined with intra-carotid administration of magnesium sulfate can provide better protection against ischemic damage than either treatment alone.
10. Combination therapy improved short-term neurological outcomes after focal cerebral ischemia.
11. Selective brain hypothermia combined with intra-carotid infusion of magnesium sulfate can significantly reduce concentrations of MMP-9and Evans blue, decrease brain water content, protect the blood-brain barrier, and inhibit vasogenic edema48h after ischemia.
12. Combined with intra-carotid magnesium sulfate could prolong the therapeutic time window of selective hypothermia for acute focal cerebral ischemia.
建立大鼠颈内动脉冷生理盐水灌注选择性脑部低温模型,探讨冷生理盐水灌注对大鼠生理指标以及局部脑组织的影响,评价本选择性脑部降温方案的安全性。采用经过激光多普勒筛选的大鼠3h大脑中动脉闭塞(middle cerebral artery occlusion, MCAO)模型,探讨颈内动脉冷生理盐水灌注对梗死体积、脑水肿、急性期神经功能预后的影响,评价选择性脑部低温对急性局灶性脑缺血的治疗作用。
采用经激光多普勒筛选的大鼠MCAO模型,予颈内动脉灌注不同剂量的硫酸镁,探讨硫酸镁对梗死体积、神经功能预后、脑含水量的影响,评价颈内动脉灌注硫酸镁对急性局灶性脑缺血的治疗效果,并确定局部灌注硫酸镁的最佳治疗剂量。
利用激光多普勒筛选的大鼠MCAO模型,在局灶性脑缺血后3h予局部灌注治疗,探讨选择性脑部低温联合颈内动脉灌注硫酸镁对梗死体积、急性期神经功能预后、脑含水量、脑组织伊文思蓝含量、血清MMP-9浓度的影响。在缺血3h再灌注后不同的时间给予治疗,探讨联合方案对选择性脑部低温治疗脑缺血时间窗的影响。
方法
采用随机设计,将58只SPF级雄性Sprgue-Dawley大鼠随机分至以下六组：假手术组(n=5),正常大鼠灌注组(n=5),梗死组(n=12),局部低温组(n=12),局部常温组(n=12),静脉低温组(n=12)。正常灌注组以及局部低温组大鼠采用颈内动脉置管,以0.4m1/min速度灌注15℃生理盐水持续20min,记录灌注前后的脑温、肛温,探索选择性低温治疗对脑温、肛温的影响以及两者之间的关系。比较选择性低温过程中心率、平均动脉压、红细胞压积、钠离子浓度、氯离子浓度、钾离子浓度、血糖以及血气指标的变化,分析脑温变化与各指标的关系。观察灌注后脑组织的形态改变以及测量灌注后脑含水量情况。制作大鼠MCAO模型,应用激光多普勒筛选入组动物,入选的造模动物根据分组予以不同的灌注方案,比较各组各时间点生理指标的差异。术后48h各组脑组织行TTC染色以及脑含水量测定,比较各组相对梗死体积以及脑含水量之间的差异。术后24h以及48h行mNSS评分评价各组缺血后神经功能损害程度,比较各组间以及各组内两个时间评分的差异。
采用随机设计,78只大鼠随机分入以下各组：假手术组(n=6)、梗死组(n=12)、生理盐水组(n=12)、硫酸镁A组(n=12)、硫酸镁B(n=12)、硫酸镁C组(n=12)、硫酸镁D组(n=12)。硫酸镁灌注组根据分组分别给予四个治疗剂量的硫酸镁(60mg/kg,90mg/kg,120mg/kg,150mg/kg)。制作大鼠MCAO模型,应用激光多普勒筛选入组动物,入选的造模动物根据分组予以不同的灌注治疗方案。硫酸镁灌注组大鼠在MCAO缺血2h再灌注同时以0.4ml/min速度灌注37℃硫酸镁(不同剂量)持续20min。生理盐水灌注组大鼠在MCAO缺血2h以后以同样的速度灌注37℃生理盐水持续20min。比较各组术前、灌注前、灌注后的心率、平均动脉压、血气分析指标、红细胞压积以及血糖水平。比较各组术前、术后、再灌注60min、再灌注120min、再灌注24h以及再灌注48h的肛温水平。在术后48h处死动物取脑切片行TTC染色,比较各组动物的相对梗死体积。取脑用干湿重法测量脑含水量,比较各组缺血后的脑组织含水量。在术后24h、48h进行神经功能检查,比较各组之间以及各组不同检查时间点之间的mNSS评分。
采用随机设计,152只动物被随机分成6组：假手术组(n=8)、梗死组(n=16)、常温盐水组(n=16)、常温镁组(n=16)、低温盐水组(n=48)、低温镁组(n=48),低温盐水组及低温镁组根据不同的低温灌注治疗时间(再灌注立即、再灌注后1h、再灌注后2h)再分为三个亚组。各组制作MCAO模型,应用激光多普勒筛选入组动物。入选的动物在缺血后予以不同的灌注方案,比较各组各时间点生理指标的差异,术后48h行TTC染色,称量脑组织干湿重,比较各组的相对梗死体积以及脑含水量。采用酶标仪测定脑组织伊文思蓝含量,采用Elisa法测量血清MMP-9浓度,比较各组之间的差异。
结果
冷生理盐水灌注前后各个时间点之间的脑温有显著差异(F=2035.541,P<0.001)。肛温在灌注过程略微下降,但灌注前后不同时间点肛温的差异无统计学意义(F=1.448,P>0.05)。从各个时间点看,灌注前脑温与肛温无显著差异(P>0.05),但低温灌注开始后脑温始终显著低于肛温(P<0.05)。低温灌注前后以及不同部位之间存在交互效应(F=1100.437,P<0.001)。在颈内动脉冷生理盐水灌注过程中脑温与肛温无相关性(r=0.169,P=0.078)。灌注前后各个时间点心率、平均动脉压、血气分析指标、红细胞压积、血糖、血钠、血氯以及血钾均无显著差异(均P>0.05),灌注过程脑温与各指标之间均无相关关系(均P>0.05)。正常灌注组48h后大脑TTC染色以及HE染色均无明显异常,脑含水量与假手术组无显著差异,48h mNSS评分0分。各组MCAO入选的大鼠基线资料均衡(均P>0.05)。灌注前后不同观察时间点之间脑温有显著的差异(F=386.698,P=0.000),不同组别之间的脑温存在显著差异(F=5480.737,P=0.000),且不同组别的脑温在不同的观察时间点变化的趋势不同(F=334.817,P=0.000)。从各个观察时间点看,在灌注前各个实验组脑温无显著差异(P>0.05),从灌注开始5min时局部低温组的脑温显著低于其他组别(P<0.001),在灌注持续20min时脑温降至最低水平,停止灌注后脑温逐渐回升,在80min时脑温与其他组别脑温无显著差异(P>0.05)。各个组别之间的肛温无显著差异(P>0.05)。各组之间梗死体积的差异具有统计学意义(F=124.402,P<0.001),局部低温组的梗死体积显著低于其余各组(均P<0.05)。各组间24h与48h mNSS评分差异有统计学意义。(F值分别为9.296,10.303,均P=0.000),局部低温组mNSS评分显著低于其它各组(均P<0.05),局部低温组24h与48h mNSS评分之间有显著差异(P<0.05)。各组脑含水量的差异有统计学意义(F=24.087,P=0.000),梗死组及各治疗组的脑含水量均显著高于假手术组(P>0.05),局部低温组的脑含水量显著低于梗死组(P<0.05)。
重复测量方差分析的结果表明,不同时间点的心率无显著差异(F=1.118,P=0.334),不同组别心率有显著差异(F=5.003,P=0.002),不同组别的心率随着不同时间点的变化趋势不同(F=4.053,P=0.000)。从各时间点看,灌注后各组的心率差异有统计学意义(F=9.588,P=0.000),且硫酸镁D组的心率显著低于其他各组的心率水平(均P<0.05)。不同时间点与不同组别的平均动脉压无显著差异(F值分别为1.555与1.613,P值分别为0.220,0.187),平均动脉压在不同的组别不同观察时间变化的趋势不同(F=2.287,P=0.024)。从各个时间点看,灌注后各个组间的平均动脉压存在显著差异(F=4.533,P=0.003),硫酸镁D组的平均动脉压显著低于梗死组、生理盐水组、硫酸镁A组与B组(均P<0.05)。血气指标、红细胞压积、血糖水平在不同时间点、不同组别间的差异均无统计学意义。术前及术后不同阶段的肛温值有显著差异(F=3.259,P=0.008),不同组别肛温无显著差异(F=2.345,P=0.065)。在各个检查时间点内,各组别肛温的差异无统计学意义(均P>0.05)。不同组别的梗死体积有显著差异(F=53.723,P=0.000)。硫酸镁C组的梗死体积最小。所有治疗组的梗死体积均显著小于梗死组(均P<0.05),所有硫酸镁治疗组的梗死体积均显著小于生理盐水组(均P<0.05),硫酸镁C组的梗死体积显著小于梗死组、生理盐水组、硫酸镁A组及硫酸镁B组(均P<0.05)。硫酸镁C组梗死体积与硫酸镁D组无显著差异(P>0.05)。各组间24h以及48h mNSS评分均有显著差异(F值分别为3.014与6.984,P值分别为0.025,0.000)。硫酸镁C组在两个时间段的mNSS评分均最低,硫酸镁C组24h mNSS显著低于梗死组(P<0.05),48h mNSS评分显著低于梗死组、生理盐水组以及硫酸镁A组(均P<0.05)。硫酸镁A组、硫酸镁C组、硫酸镁D组内48h mNSS均显著低于24h mNSS。各组别间脑含水量具有显著差异(F=12.518,P=0.000),梗死组及各治疗组的脑含水量均显著高于假手术组(均P<0.05),硫酸镁C组的脑含水量显著低于梗死组(P<0.05)。
各组之间的基线资料均衡(均P>0.05)。灌注前后不同时间之间脑温有显著差异(F=1271.447,P=0.000),不同组别之间的脑温有显著差异(F=4536.260,P=0.000),不同时间以及不同组别之间存在交互效应(F=447.427,P=0.000)。从各个时间看,灌注前各组脑温无显著差异(P>0.05),从灌注5min开始各组脑温存在显著差异(P<0.05),直至80min(停止灌注60min)时各组脑温差异无统计学意义(P>0.05)。在5min至65min间各个时间点内,低温盐水组与低温镁组的脑温均与梗死组有显著差异(P<0.05)。低温盐水组与低温镁组各个时间点的脑温均无显著差异(P>0.05)。各组之间的梗死体积有显著差异(F=48.007,P=0.000),低温镁组的梗死体积最小,低温盐水组与低温镁组梗死体积均显著小于梗死组(均P<0.05),低温镁组与低温盐水组梗死体积有显著差异(P<0.05)。各实验组24h与48h mNSS均有显著差异(F值分别为11.827,17.500,P值均为0.000)。低温镁组48h mNSS评分显著低于其他各治疗组(P<0.05)。各组脑含水量有显著差异(F=9.438,P=0.000),低温镁组的脑含水量显著低于梗死组(P<0.05)。各组脑组织伊文思蓝含量有显著差异(F=19.263,P=0.000),低温镁组的伊文思蓝含量显著低于梗死组(P<0.05)。各组间血清MMP-9含量有显著差异(F=4.740,P=0.004),低温镁组的MMP-9含量显著低于梗死组(P<0.05)。在各个治疗时间点内不同组别的梗死体积均有显著差异,F值分别为69.682,51.564,24.107,P值均为0.000。在再灌注即时以及再灌注后1h治疗,低温盐水组与低温镁组梗死体积均显著小于梗死组。(均P<0.05)。在再灌注2h治疗,仅低温镁组较梗死组显著降低梗死体积(P<0.05)。各个治疗时间点内不同组别的48h mNSS评分均有显著差异,F值分别为25.451,11.172,5.572,P值为0.000,0.000,0.011。在再灌注即时治疗,低温盐水与低温镁组mNSS评分均显著低于梗死组。在再灌注1h及2h治疗,仅低温镁组mNSS评分与梗死组有统计学差异(P<0.05)。各个治疗时间低温镁组的mNSS评分均显著低于低温盐水组(P<0.05)。在各个治疗时间点内不同组别的脑含水量均有显著差异,F值分别为17.063,26.766,28.507,P值均为0.000。在再灌注0h与1h时给予治疗,低温镁组脑含水量与梗死组有显著差异(P<0.05)。在再灌注后2h给予治疗,低温镁组脑含水量与梗死组差异无统计学意义(均P>0.05)。
结论
1.颈内动脉冷生理盐水灌注能够快速地降低脑温,并可以维持全身体温的恒定。
2.颈内动脉灌注冷生理盐水对局部脑组织无损害作用,并保持心率、平均动脉压、血气指标、红细胞压积、血糖以及电解质的稳定,该选择性脑部降温方法是安全的。
3.选择性脑部低温可以显著减少局灶性脑缺血后梗死体积并促进神经功能的恢复。
4.局灶性脑缺血后48h会出现不同程度的脑水肿,颈内动脉灌注冷生理盐水可有效减少脑水肿程度。
5.脑缺血后予颈内动脉灌注硫酸镁治疗可以显著减少缺血后脑梗死体积。
6.颈内动脉灌注硫酸镁可以减少24h和48h的mNSS,有利于MCAO术后的神经功能恢复。
7.脑缺血48h后出现明显脑水肿,而缺血后颈内动脉灌注硫酸镁可以明显减轻脑水肿程度,
8.颈内动脉灌注硫酸镁对脑缺血的治疗作用在60mg/kg-120mg/kg剂量之间呈剂量依赖性的,局部用药的最佳剂量是120mg/kg。
9.在对急性局灶性脑缺血治疗中,血管内选择性脑部低温联合颈内动脉灌注硫酸镁可显著减少脑梗死体积,在急性期起到脑保护作用,疗效优于各单独治疗。
10.血管内选择性低温联合颈内动脉灌注硫酸镁可显著改善24h和48hmNSS结果,有利于脑缺血后神经功能恢复。
11.联合治疗可以显著减少缺血再灌注后血清MMP-9浓度、脑组织EB含量以及脑含水量,有效保护血脑屏障,抑制血管源性脑水肿。
12.联用颈内动脉灌注硫酸镁可以延长血管内选择性脑部低温治疗急性局灶性脑缺血的时间窗。
Objective
To establish a selective brain hypothermia model induced by intra-carotid infusion of cold saline in rats and evaluate its safety on local brain tissue and physiological variables. To explore the effect of selective brain hypothermia on brain infarct volume, neurological functional outcomes and brain water content after brain ischemia.
This study was performed to determine the neuroprotective potentials of intra-carotid magnesium sulfate infusion to ischemic stroke and find the optimal protective dose of magnesium sulfate for local infusion using the filament model of transient MCAO in rats.
The aim of the study was to evaluate the protective effect of combination therapy with selective brain hypothermia and intra-carotid magnesium sulfate and determine whether intra-carotid infusion of cold magnesium sulfate would provide better neuroprotection against cerebral ischemia injury than cold saline infusion alone.
Methods
Fifty-eight male rats were randomly assigned into following groups:sham operated group (n=5), normal infusion group (n=5), stroke group (n=12), local hypothermic group (n=12), local normothermic group (n=12), systemic infusion group (n=12). Rats in normal infusion group and local hypothermic group received intra-carotid infusion of cold saline at the rate of0.4ml/min for20min. Both of brain and rectal temperature were monitored before, during and after cold infusion until the brain temperature returned to normal. Physiological variables including heart rate, mean arterial pressure, heamatocrit and blood gases were measured too. Brain sections were stained with HE and TTC to observe the morphological changes of brain tissue. Brain water content and neurological deficits were also evaluated. Rats with focal cerebral ischemia were given various infusions treatments following3h ischemia according to different groups. Physiological variables at different time point were compared among experimental groups. Brain infarct volume and cerebral water content were analyzed48h after MCAO. Neurological deficits were assessed using the mNSS24and48h after MCAO.
Seventy-eight rats were randomly divided into following groups:sham operated group (n=6), stroke group (n=12), saline group (n=12), magnesium sulfate group A (n=12), magnesium sulfate group B (n=12), magnesium sulfate group C (n=12), and magnesium sulfate group D (n=12). There were four dose of magnesium sulfate (60mg/kg,90mg/kg,120mg/kg,150mg/kg) were used in the study. Each animals in local infusion groups was given an intra-carotid magnesium sulfate or saline infusion overe a period of20min at the initiation of reperfusion (180-200min after onset of ischemia). Before reperfusion was established,8ml of magnesium sulfate or saline was injected slowly and continuously via a catheter, using an infusion pump to control the infusion rate at0.4ml/min. Physiological variables including heart rate, mean arterial pressure, blood gases, glucose and hemotocrit were measured before MCAO, before and after reperfusion. Rectal temperatures were continuously monitored until48h after MCAO. Infarct volume and brain water content were measured48h after MCAO. Neurological examinations were performed24h and48h after MCAO using the mNSS.
One hundred and fifty-two male rats were randomly assigned into following groups:sham operated group (n=8), stroke group (n=16), normothermic saline group (n=16), normothermic magnesium group (n=16), hypothermic saline group (n=48) and hypothermic magnesium group (n=48). Animals in hypothermic saline group and hypothermic magnesium group divided into three subgroups according to different initiation time of cold infusion. Each animal in local infusion groups was given an intra-carotid magnesium sulfate (15℃or37℃) or saline (15℃or37℃) infusion over a period of20min starting at the initiation of reperfusion (180-200min after onset of ischemia). Before reperfusion was established,8ml of magnesium sulfate (15℃or37℃) or saline (15℃or37℃) was injected slowly and continuously via a catheter, using an infusion pump to control the infusion rate at0.4ml/min for20min. Infarct volume and brain water contents were measured48h after MCAO. In a blinded manner, animals were examined for neurological deficit48h after MCAO using the mNSS. Evans blue (EB) concentrations in brain tissue were measured48h after MCAO. Concentrations of serum MMP-9were also measured48h after MCAO using Elisa.
Results
Significant differences were found in brain temperatures among different time points (F=2035.541, P<0.001). There was no significant difference in rectal temperatures among different time points (F=1.448, P>0.05). At each time point after cold infusion, brain temperature was significantly lower than rectal temperature (P>0.05). There was no correlation between brain temperature and rectal temperature during the monitoring periods (r=0.220, P=0.152). Physiological variables including heart rate, mean arterial pressure, blood gases, glucose and hemocrit were not significantly different among each time point. Moreover, there were no correlation between brain temperature and all physiological variables. No significant morphological abnormal was found in brain sections stained with TTC and HE. Animals received local cold infusion did not show neurological deficits48h after infusion. All baseline data was balanced between different groups (all P>0.05). Brain temperatures were significantly different before and after local infusion among groups (F values were386.698and5480.737, both P=0.000). In the local hypothermic group, brain temperature was reduced to33-34℃within5-10min and significantly lower than that in other groups after5min of commencing infusion, and this significantly low temperature was maintained to nearly60min after infusion continued. There was no significant difference in rectal temperatures among groups. A significant difference was found in infarct volume among groups (F=124.402, P<0.001). Animals treated with local cold infusion had a significantly smaller infarct volume compared with other groups (P<0.05). Both of24h and48h mNSS were significantly different among all groups (F values were9.296and10.303, all P=0.000). Both24h and48h mNSS in local hypothermic group was significantly lower than that in other groups. There was a significant difference between24h and48h mNSS in local hypothermic group. Brain water contents were significantly different among all goups (F=24.087, P=0.000). Local hypothermic group siginificantly decreased brain water contents compared to stroke group (P<0.05).
Heart rate of the animals differ significantly during the period of experiment among six study groups (F=6.185, P=0.000). After reperfusion, a significant difference was found in heart rate among study groups (F=9.588, P=0.000).Heart rate in magnesium sulfate group D decreased significantly as compared to other groups (all P<0.05). Mean arterial pressure did not significantly different during the monitored period among the study group (F value was1.555and1.613, P was0.220and0.187). After reperfusion, there was a significant difference in mean arterial pressure among groups (F=4.533, P=0.003). Mean arterial pressure in magnesium sulfate group D was significantly lower than that in stroke group, saline group, magnesium sulfate group A and B (all P<0.05). Although a significant difference in rectal temperatures was found during the monitoring period, there was no significant difference between the experimental group at each time point. The other physiological parameters of the animals were kept within normal physiological limits during the course of experiments and did not differ significantly among the study groups. There was a significant difference in infarct volume among all groups (F=53.723, P=0.000). Magnesium sulfate group C revealed the smallest infarct volume. Infarct volume in all treatment groups were significantly smaller than that in stroke group (all P<0.05). Animals treated with intra-carotid magnesium sulfate revealed decrease infarct volume compared with saline infusion (all P<0.05). Infarct volume in magnesium sulfate group C significantly smaller than that in stroke group, saline group, magnesium sulfate group A and B (all P<0.05). There was no significant difference between magnesium sulfate group C and D (P>0.05). There was a significant difference in24h and48h mNSS among all groups (F value was3.014and6.984, P was0.025and0.000). Magnesium sulfate group C revealed the least mNSS in24h and48h after MCAO. At24h after MCAO, mNSS in magnesium sulfate group C significantly less than that in stroke group (all P<0.05). At48h after MCAO, magnesium sulfate group C significantly less than stroke group, saline group and magnesium sulfate group A (all P<0.05). There was a significant difference in cerebral water contents among all groups (F=12.518, P=0.000). Brain water contents in stroke groups were significantly higher than that in sham-operated group (all P<0.05). Magnesium sulfate group C demonstrated significantly reduced brain edema compared to the stroke group (P<0.05).
Baseline data among groups were balanced (all P>0.05). Brain temperatures were significantly different during the monitoring periods among all the groups (F=447.427, P=0.000). At five minutes after local infusion, brain temperatures in cold infusion groups significantly lower than that in stroke group, this significantly low temperature maintained until60min after stopping of infusion. Brain temperatures did not differ significantly between two cold infusion groups at any time point. There was a significantly difference in infarct volume among all groups (F=48.007, P=0.000). Animals in hypothermic magnesium sulfate group revealed the least infarct volume. Infarct volume in hypothermic magnesium sulfate group was significantly smaller than that in stroke group and hypothermic saline group (P<0.05). There was a significant difference in neurological function among groups at24h and48h after MCAO (F value was11.827and17.500, all P=0.000). Rats in hypothermic magnesium group had a significantly less mNSS than other groups at48h after MCAO (P<0.05). Brain water contents were significantly different among all groups (F=9.438, P=0.000). Hypothermic magnesium group significantly decreased brain water contents compared to stroke group. Concentrations of EB was significantly different among groups (F=19.263, P=0.000). Rats in hypothermic magnesium group demonstrated less EB concentrations than stroke group (P<0.05). Serum MMP-9concentration were significantly different among groups (F=4.740, P=0.004). Serum MMP-9in hypothermic magnesium group was less than that in stroke group (P<0.05). At each treatment time point, there was a significant difference in infarct volume among all group (F value was69.682,51.564,24.107, all P=0.000). Both hypothermic saline and hypothermic magnesium significantly decreased infarct volume compared to stroke group when local infusion begined with reperfusion or1h after reperfusion (all P<0.05). At2h after reperfusion, only hypothermic magnesium group significantly reduced infarct volume compared to stroke group (P<0.05). At each treatment time point, neurological functions were significantly different among all groups at48h after MCAO (F value was25.451,11.172,5.572, P value was0.000,0.000,0.011). Both hypothermic saline group and hypothermic magnesium group significantly improved neurological outcome compared to stroke group when local infusion commenced at the beginning of reperfusion (P<0.05). Only animals treated with cold magnesium can significantly reduced mNSS compared with stroke group when treatments begin with1h and2h after reperfusion (P<0.05). A significant difference was found in brain water contents among groups at each treatment time point (F value was17.063,26.766,28.507, P=0.000). Brain water content in hypothermic magnesium group was significantly less than that in stroke group when local infusions given at reperfusion and1h after reperfusion (P<0.05). There was no significant difference in brain water content between stroke group and hypothermic groups when treatments delayed to2h after MCAO.
Conclusion
1. Selective brain hypothermia induced by intra-carotid cold saline infusion can quickly and effectively reduce the brain temperature, while maintain the rectal temperature within normal range.
2. Intra-carotid cold saline infusion did not have a harm effect on brain tissue and did not affect physiological variables. Intra-carotid infusion of cold saline is a relatively safe cooling method.
3. Intra-carotid cold saline infusion significantly reduced brain infarct volume and improved neurological functional outcomes after brain ischemia.
4. Brain water content in all stroke groups was significantly higher than that in sham-operated group48h after MCAO. Intra-carotid cold saline infusion can effectively reduce the cerebral edema after brain ischemia.
5. Intra-carotid magnesium sulfate infusion can effectively reduce infarct volume following acute focal cerebral ischemia.
6. Intra-carotid infusion of magnesium sulfate improved short-term functional outcomes after middle cerebral artery occlusion.
7. Intra-carotid magnesium sulfate infusion reduced cerebral edema48h after ischemic stroke.
8. Neuroprotective effect of magnesium sulfate in the dose of60mg/kg-120mg/kg was dose-dependent in cerebral ischemia. The optimal protective dose was120mg/kg.
9. Selective endovascular hypothermia combined with intra-carotid administration of magnesium sulfate can provide better protection against ischemic damage than either treatment alone.
10. Combination therapy improved short-term neurological outcomes after focal cerebral ischemia.
11. Selective brain hypothermia combined with intra-carotid infusion of magnesium sulfate can significantly reduce concentrations of MMP-9and Evans blue, decrease brain water content, protect the blood-brain barrier, and inhibit vasogenic edema48h after ischemia.
12. Combined with intra-carotid magnesium sulfate could prolong the therapeutic time window of selective hypothermia for acute focal cerebral ischemia.
引文
[1]Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest[J]. N Engl J Med,2002,346(8):549-56.
[2]Bernard, S.A., T.W. Gray, M.D. Buist, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia[J]. N Engl J Med, 2002,346(8):557-63.
[3]Zeiner, A., M. Holzer, F. Sterz, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group[J]. Stroke,2000, 31(1):86-94.
[4]Moran, J.L.,P.J. Solomon. Application of therapeutic hypothermia in the intensive care unit[J]. Intensive Care Med,2004,30(12):2288; author reply 2287.
[5]Fay. Observations on generalized refrigeration in cases of severe cerebral trauma[J]. Assoc Res Nerv Ment Dis Proc,1943,24:611-619.
[6]Ravitch, M.M., R. Lane, P. Safar, et al. Lightning stroke. Report of a case with recovery after cardiac massage and prolonged artificial respiration[J]. N Engl J Med,1961,264:36-8.
[7]Weinrauch, V., P. Safar, S. Tisherman, et al. Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs[J]. Stroke,1992,23(10):1454-62.
[8]Gunn, A.J.,M. Thoresen. Hypothermic neuroprotection[J]. NeuroRx,2006, 3(2):154-69.
[9]Zhang, Y., K.C. Wong,Z. Zhang. The effect of intraischemic mild hypothermia on focal cerebral ischemia/reperfusion injury[J]. Acta Anaesthesiol Sin,2001, 39(2):65-9.
[10]Hoffman, P.J., D.B. Milliken, L.C. Gregg, et al. Molecular characterization of uterine fibroids and its implication for underlying mechanisms of pathogenesis[J]. Fertil Steril,2004,82(3):639-49.
[11]Busto, R., M.Y. Globus, W.D. Dietrich, et al. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain[J]. Stroke,1989,20(7):904-10.
[12]Baker, C.J., A.J. Fiore, V.I. Frazzini, et al. Intraischemic hypothermia decreases the release of glutamate in the cores of permanent focal cerebral infarcts[J]. Neurosurgery,1995,36(5):994-1001; discussion 1001-2.
[13]Phanithi, P.B., Y. Yoshida, A. Santana, et al. Mild hypothermia mitigates post-ischemic neuronal death following focal cerebral ischemia in rat brain: immunohistochemical study of Fas, caspase-3 and TUNEL[J]. Neuropathology,2000,20(4):273-82.
[14]Niwa, M., A. Hara, T. Iwai, et al. Relationship between magnitude of hypothermia during ischemia and preventive effect against post-ischemic DNA fragmentation in the gerbil hippocampus[J]. Brain Res,1998,794(2): 338-42.
[15]Reuler, J.B. Hypothermia:pathophysiology, clinical settings, and management[J]. Ann Intern Med,1978,89(4):519-27.
[16]Frank, S.M., L.A. Fleisher, M.J. Breslow, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial[J]. JAMA,1997,277(14):1127-34.
[17]Schmied, H., A. Schiferer, D.I. Sessler, et al. The effects of red-cell scavenging, hemodilution, and active warming on allogenic blood requirements in patients undergoing hip or knee arthroplasty[J]. Anesth Analg, 1998,86(2):387-91.
[18]Sessler, D.I., C.I. Olofsson,E.H. Rubinstein. The thermoregulatory threshold in humans during nitrous oxide-fentanyl anesthesia[J]. Anesthesiology,1988, 69(3):357-64.
[19]Wenisch, C., E. Narzt, D.I. Sessler, et al. Mild intraoperative hypothermia reduces production of reactive oxygen intermediates by polymorphonuclear leukocytes[J]. Anesth Analg,1996,82(4):810-6.
[20]Gadkary, C.S., P. Alderson,D.F. Signorini. Therapeutic hypothermia for head injury[J]. Cochrane Database Syst Rev,2002(1):CD001048.
[21]Kurz, A., D.I. Sessler,R. Lenhardt. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group[J]. N Engl J Med,1996,334(19): 1209-15.
[22]Morgan, D.B.,R.M. Young. Acute transient hypokalaemia:new interpretation of a common event [J]. Lancet,1982,2(8301):751-2.
[23]Koht, A., R. Cane,L.J. Cerullo. Serum potassium levels during prolonged hypothermia[J]. Intensive Care Med,1983,9(5):275-7.
[24]Bloch, M. Cerebral effects of rewarming following prolonged hypothermia: significance for the management of severe cranio-cerebral injury and acute pyrexia[J]. Brain,1967,90(4):769-84.
[25]Schwab, S., S. Schwarz, M. Spranger, et al. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction [J]. Stroke, 1998,29(12):2461-6.
[26]Schwab, S., D. Georgiadis, J. Berrouschot, et al. Feasibility and safety of moderate hypothermia after massive hemispheric infarction[J]. Stroke,2001, 32(9):2033-5.
[27]Maloney, S.K., A. Fuller, G. Mitchell, et al. Rectal temperature measurement results in artifactual evidence of selective brain cooling[J]. Am J Physiol Regul Integr Comp Physiol,2001,281(1):R108-14.
[28]Wang, H., W. Olivero, G. Lanzino, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet[J]. J Neurosurg,2004,100(2): 272-7.
[29]Qiu, W., H. Shen, Y. Zhang, et al. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury[J]. J Clin Neurosci,2006,13(10):995-1000.
[30]Abou-Chebl, A., M.A. DeGeorgia, J.C. Andrefsky, et al. Technical refinements and drawbacks of a surface cooling technique for the treatment of severe acute ischemic stroke[J]. Neurocrit Care,2004,1(2):131-43.
[31]Corbett, R.J.,A.R. Laptook. Failure of localized head cooling to reduce brain temperature in adult humans[J]. Neuroreport,1998,9(12):2721-5.
[32]Neimark, M.A., A.A. Konstas, J.H. Choi, et al. Local control of temperature in a theoretical human model of selective brain cooling[J]. Conf Proc IEEE Eng Med Biol Soc,2007,2007:6349-52.
[33]Cheng, H., J. Shi, L. Zhang, et al. Epidural cooling for selective brain hypothermia in porcine model[J]. Acta Neurochir (Wien),2006,148(5): 559-64; discussion 564.
[34]Parkins, W.M., J.M. Jensen,H.M. Vars. Brain cooling in the prevention of brain damage during periods of circulatory occlusion in dogs[J]. Ann Surg, 1954,140(3):284-9.
[35]Ohta, T., I. Sakaguchi, L.W. Dong, et al. Selective cooling of brain using profound hemodilution in dogs[J]. Neurosurgery,1992,31(6):1049-54; discussion 1054-5.
[36]Schwartz, A.E., J.G. Stone, A.D. Finck, et al. Isolated cerebral hypothermia by single carotid artery perfusion of extracorporeally cooled blood in baboons[J]. Neurosurgery,1996,39(3):577-81; discussion 581-2.
[37]Jiang, J.Y., W. Xu, P.F. Yang, et al. Marked protection by selective cerebral profound hypothermia after complete cerebral ischemia in primates[J]. J Neurotrauma,2006,23(12):1847-56.
[38]Wen, Y.S., M.S. Huang, M.T. Lin, et al. Rapid brain cooling by hypothermic retrograde jugular vein flush[J]. J Trauma,2005,58(3):577-81.
[39]Neimark, M.A., A.A. Konstas, J.H. Choi, et al. The role of intracarotid cold saline infusion on a theoretical brain model incorporating the circle of willis and cerebral venous return[J]. Conf Proc IEEE Eng Med Biol Soc,2007,2007: 1140-3.
[40]Slotboom, J., C. Kiefer, C. Brekenfeld, et al. Locally induced hypothermia for treatment of acute ischaemic stroke:a physical feasibility study [J]. Neuroradiology,2004,46(11):923-34.
[41]Choi, J.H., R.S. Marshall, M.A. Neimark, et al. Selective brain cooling with endovascular intracarotid infusion of cold saline:a pilot feasibility study [J]. AJNR Am J Neuroradiol,2010,31(5):928-34.
[42]Ding, Y., J. Li, X. Luan, et al. Local saline infusion into ischemic territory induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion[J]. Neurosurgery,2004,54(4):956-64; discussion 964-5.
[43]Ding, Y, J. Li, Q. Lai, et al. Motor balance and coordination training enhances functional outcome in rat with transient middle cerebral artery occlusion[J]. Neuroscience,2004,123(3):667-74.
[44]Toung, T.J., A. Bhardwaj, V.L. Dawson, et al. Neuroprotective FK506 does not alter in vivo nitric oxide production during ischemia and early reperfusion in rats[J]. Stroke,1999,30(6):1279-85.
[45]Rusa, R., N.J. Alkayed, B.J. Crain, et al.17beta-estradiol reduces stroke injury in estrogen-deficient female animals[J]. Stroke,1999,30(8):1665-70.
[46]Schabitz, W.R., C. Berger, R. Kollmar, et al. Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia[J]. Stroke,2004,35(4):992-7.
[47]Nishi, H., T. Watanabe, H. Sakurai, et al. Effect of MCI-186 on brain edema in rats[J]. Stroke,1989,20(9):1236-40.
[1]Vande Linde, A.M., M. Chopp, H. Chen, et al. Chronic changes in the brain Mg2+concentration after forebrain ischemia in the rat[J]. Metab Brain Dis, 1991,6(4):199-206.
[2]Vink, R., D.L. Heath,T.K. McIntosh. Acute and prolonged alterations in brain free magnesium following fluid percussion-induced brain trauma in rats[J]. J Neurochem,1996,66(6):2477-83.
[3]Lee, M.S., Y.S. Wu, D.Y. Yang, et al. Significantly decreased extracellular magnesium in brains of gerbils subjected to cerebral ischemia[J]. Clin Chim Acta,2002,318(1-2):121-5.
[4]Muir, J.K., R. Raghupathi, D.L. Emery, et al. Postinjury magnesium treatment attenuates traumatic brain injury-induced cortical induction of p53 mRNA in rats[J]. Exp Neurol,1999,159(2):584-93.
[5]van den Bergh, W.M., J.K. Zuur, N.A. Kamerling, et al. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage[J]. J Neurosurg,2002,97(2):416-22.
[6]Muir, K.W. Magnesium for neuroprotection in ischaemic stroke:rationale for use and evidence of effectiveness [J]. CNS Drugs,2001,15(12):921-30.
[7]van den Bergh, W.M., A. Algra, F. van Kooten, et al. Magnesium sulfate in aneurysmal subarachnoid hemorrhage:a randomized controlled trial[J]. Stroke, 2005,36(5):1011-5.
[8]Grubbs, R.D.,M.E. Maguire. Magnesium as a regulatory cation:criteria and evaluation[J]. Magnesium,1987,6(3):113-27.
[9]Nowak, L., P. Bregestovski, P. Ascher, et al. Magnesium gates glutamate-activated channels in mouse central neurones[J]. Nature,1984, 307(5950):462-5.
[10]Cotton, D.B., M. Hallak, C. Janusz, et al. Central anticonvulsant effects of magnesium sulfate on N-methyl-D-aspartate-induced seizures[J]. Am J Obstet Gynecol,1993,168(3 Pt 1):974-8.
[11]Kaya, M., S. Gulturk, I. Elmas, et al. The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats[J]. Life Sci,2004,76(2):201-12.
[12]Chi, O.Z., P. Pollak,H.R. Weiss. Effects of magnesium sulfate and nifedipine on regional cerebral blood flow during middle cerebral artery ligation in the rat[J]. Arch Int Pharmacodyn Ther,1990,304:196-205.
[13]Kemp, P.A., S.M. Gardiner, T. Bennett, et al. Magnesium sulphate reverses the carotid vasoconstriction caused by endothelin-Ⅰ, angiotensin Ⅱ and neuropeptide-Y, but not that caused by NG-nitro-L-arginine methyl ester, in conscious rats[J]. Clin Sci (Lond),1993,85(2):175-81.
[14]Izumi, Y., S. Roussel, E. Pinard, et al. Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats[J]. J Cereb Blood Flow Metab,1991,11(6):1025-30.
[15]Schmid-Elsaesser, R., S. Zausinger, E. Hungerhuber, et al. Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia[J]. Neurosurgery,1999,44(1):163-71; discussion 171-2.
[16]Yang, Y, Q. Li, F. Ahmad, et al. Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat[J]. Neurosci Lett,2000,285(2):119-22.
[17]Kinoshita, Y, T. Ueyama, E. Senba, et al. Expression of c-fos, heat shock protein 70, neurotrophins, and cyclooxygenase-2 mRNA in response to focal cerebral ischemia/reperfusion in rats and their modification by magnesium sulfate[J]. J Neurotrauma,2001,18(4):435-45.
[18]Lin, J.Y., S.Y. Chung, M.C. Lin, et al. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique[J]. Life Sci,2002,71(7):803-11.
[19]Zhu, H.D., R. Martin, B. Meloni, et al. Magnesium sulfate fails to reduce infarct volume following transient focal cerebral ischemia in rats[J]. Neurosci Res,2004,49(3):347-53.
[20]Westermaier, T., S. Zausinger, A. Baethmann, et al. Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats[J]. Acta Neurochir (Wien),2005,147(5):525-32; discussion 532.
[21]Marinov, M.B., K.S. Harbaugh, P.J. Hoopes, et al. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia[J]. J Neurosurg,1996,85(1):117-24.
[22]Lee, E.J., M.Y. Lee, G.L. Chang, et al. Delayed treatment with magnesium: reduction of brain infarction and improvement of electrophysiological recovery following transient focal cerebral ischemia in rats[J]. J Neurosurg, 2005,102(6):1085-93.
[23]Johansson, B.W. Magnesium infusion in decompensated hypomagnesemic patients[J]. Acta Pharmacol Toxicol (Copenh),1984,54 Suppl 1:125-8.
[24]Muir, K.W., K.R. Lees, I. Ford, et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial):randomised controlled trial [J]. Lancet, 2004,363(9407):439-45.
[25]Muir, K.W.,K.R. Lees. Dose optimization of intravenous magnesium sulfate after acute stroke[J]. Stroke,1998,29(5):918-23.
[26]Lampl, Y., R. Gilad, D. Geva, et al. Intravenous administration of magnesium sulfate in acute stroke:a randomized double-blind study [J]. Clin Neuropharmacol,2001,24(1):11-5.
[27]Aslanyan, S., C.J. Weir, K.W. Muir, et al. Magnesium for treatment of acute lacunar stroke syndromes:further analysis of the IMAGES trial[J]. Stroke, 2007,38(4):1269-73.
[28]Saver, J.L., C. Kidwell, M. Eckstein, et al. Prehospital neuroprotective therapy for acute stroke:results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial[J]. Stroke,2004,35(5):e106-8.
[29]Meloni, B.P., H. Zhu,N.W. Knuckey. Is magnesium neuroprotective following global and focal cerebral ischaemia? A review of published studies[J]. Magnes Res,2006,19(2):123-37.
[30]Rother, J. Neuroprotection does not work![J]. Stroke,2008,39(2):523-4.
[31]Joshi, S., P.M. Meyers,E. Ornstein. Intracarotid delivery of drugs:the potential and the pitfalls[J]. Anesthesiology,2008,109(3):543-64.
[32]Bazin, J.E., P. Picard, J. Gabrillargues, et al. Propofol administered via the carotid artery to achieve a Wada test[J]. Can J Anaesth,1998,45(7):707-8.
[33]Uemura, S., Y. Matsukado, S. Yoshioka, et al. [Prevention of ocular toxicity by the intra-carotid perfusion of anticancer agents in the treatment of malignant glioma. Usefulness of a remodeled epidural catheter and selective CT enhancements][J]. Neurol Med Chir (Tokyo),1986,26(6):461-7.
[34]Myklebust, A.T., A. Helseth, K. Breistol, et al. Nude rat models for human tumor metastasis to CNS. Procedures for intracarotid delivery of cancer cells and drugs[J]. J Neurooncol,1994,21(3):215-24.
[35]Jahan, R. Hyperacute therapy of acute ischemic stroke:intraarterial thrombolysis and mechanical revascularization strategies [J]. Tech Vase Interv Radiol,2005,8(2):87-91.
[36]Taussky, P., R.G. Tawk, W.P. Daugherty, et al. Medical therapy for ischemic stroke:review of intravenous and intra-arterial treatment options[J]. World Neurosurg,76(6 Suppl):S9-15.
[37]Nishi, H., T. Watanabe, H. Sakurai, et al. Effect of MCI-186 on brain edema in rats[J]. Stroke,1989,20(9):1236-40.
[38]Kermer, P., N. Klocker,M. Bahr. Neuronal death after brain injury. Models, mechanisms, and therapeutic strategies in vivo[J]. Cell Tissue Res,1999, 298(3):383-95.
[39]Johnson, J.W.,P. Ascher. Voltage-dependent block by intracellular Mg2+of N-methyl-D-aspartate-activated channels[J]. Biophys J,1990,57(5):1085-90.
[40]Budd, S.L. Mechanisms of neuronal damage in brain hypoxia/ischemia:focus on the role of mitochondrial calcium accumulation[J]. Pharmacol Ther,1998, 80(2):203-29.
[41]Frandsen, A., A. Schousboe. Effect of magnesium on NMD A mediated toxicity and increases in [Ca2+]i and cGMP in cultured neocortical neurons:evidence for distinct regulation of different responses[J]. Neurochem Int,1994,25(4): 301-8.
[42]Iseri, L.T.,J.H. French. Magnesium:nature's physiologic calcium blocker[J]. Am Heart J,1984,108(1):188-93.
[43]Kemp, P.A., S.M. Gardiner, J.E. March, et al. Assessment of the effects of endothelin-1 and magnesium sulphate on regional blood flows in conscious rats, by the coloured microsphere reference technique[J]. Br J Pharmacol, 1999,126(3):621-6.
[44]Aisenbrey, G.A., E. Corwin,V. Catanzarite. Effect of magnesium sulfate on the vascular actions of norepinephrine and angiotensin II[J]. Am J Perinatol,1992, 9(5-6):477-80.
[45]Torregrosa, G, A.J. Perales, J.B. Salom, et al. Different effects of Mg2+on endothelin-1-and 5-hydroxytryptamine-elicited responses in goat cerebrovascular bed[J]. J Cardiovasc Pharmacol,1994,23(6):1004-10.
[46]Ram, Z., M. Sadeh, I. Shacked, et al. Magnesium sulfate reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in rats[J]. Stroke,1991,22(7):922-7.
[47]Perales, A.J., G. Torregrosa, J.B. Salom, et al. In vivo and in vitro effects of magnesium sulfate in the cerebrovascular bed of the goat[J]. Am J Obstet Gynecol,1991,165(5 Pt 1):1534-8.
[48]Alborch, E., J.B. Salom, A.J. Perales, et al. Comparison of the anticonstrictor action of dihydropyridines (nimodipine and nicardipine) and Mg2+in isolated human cerebral arteries[J]. Eur J Pharmacol,1992,229(1):83-9.
[49]Adams, J.H.,J.R. Mitchell. The effect of agents which modify platelet behaviour and of magnesium ions on thrombus formation in vivo[J]. Thromb Haemost,1979,42(2):603-10.
[50]Kurgan, A., S.D. Gertz, R.S. Wajnberg, et al. Effect of magnesium sulfate on platelet deposition in rabbits following temporary arterial occlusion with surgical clips[J]. Surgery,1980,87(4):390-6.
[51]Ravn, H.B., H. Vissinger, S.D. Kristensen, et al. Magnesium inhibits platelet activity-an infusion study in healthy volunteers[J]. Thromb Haemost,1996, 75(6):939-44.
[52]Kynczl-Leisure, M.,L.A. Cibils. Increased bleeding time after magnesium sulfate infusion[J]. Am J Obstet Gynecol,1996,175(5):1293-4.
[53]ISIS-4:a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group[J]. Lancet,1995,345(8951):669-85.
[54]Green, A.R.,A. Shuaib. Therapeutic strategies for the treatment of stroke[J]. Drug Discov Today,2006,11(15-16):681-93.
[55]Lees, K.R., J.A. Zivin, T. Ashwood, et al. NXY-059 for acute ischemic stroke[J]. N Engl J Med,2006,354(6):588-600.
[56]Shuaib, A., K.R. Lees, P. Lyden, et al. NXY-059 for the treatment of acute ischemic stroke[J]. N Engl J Med,2007,357(6):562-71.
[57]Use of anti-ICAM-1 therapy in ischemic stroke:results of the Enlimomab Acute Stroke Trial[J]. Neurology,2001,57(8):1428-34.
[58]Wada, J..T. Rasmussen. Intracarotid injection of sodium amytal for the lateralization of cerebral speech dominance.1960[J]. J Neurosurg,2007, 106(6):1117-33.
[59]Dedrick, R.L., E.H. Oldfield,J.M. Collins. Arterial drug infusion with extracorporeal removal. I. Theoretic basis with particular reference to the brain[J]. Cancer Treat Rep,1984,68(2):373-80.
[60]Neuwelt, E.A., M. Pagel, P. Barnett, et al. Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification[J]. Cancer Res,1981,41(11 Pt 1):4466-70.
[61]Joshi, S., C.W. Emala,J. Pile-Spellman. Intra-arterial drug delivery:a concise review[J]. J Neurosurg Anesthesiol,2007,19(2):111-9.
[62]Gobin, Y.P., T.F. Cloughesy, K.L. Chow, et al. Intraarterial chemotherapy for brain tumors by using a spatial dose fractionation algorithm and pulsatile delivery[J]. Radiology,2001,218(3):724-32.
[63]Yamashita, J., H. Handa, Y. Tokuriki, et al. Intra-arterial ACNU therapy for malignant brain tumors. Experimental studies and preliminary clinical results[J]. J Neurosurg,1983,59(3):424-30.
[64]Joshi, S., W.L. Young, J. Pile-Spellman, et al. The feasibility of intracarotid adenosine for the manipulation of human cerebrovascular resistance [J]. Anesth Analg,1998,87(6):1291-8.
[65]Jones, D.R., S.D. Hall, E.K. Jackson, et al. Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding[J]. J Pharmacol Exp Ther, 1988,245(3):816-22.
[66]Joshi, S., M. Wang, J.J. Etu, et al. Bolus configuration affects dose requirements of intracarotid propofol for electroencephalographic silence[J]. Anesth Analg,2006,102(6):1816-22.
[67]Khatri, P., J. Neff, J.P. Broderick, et al. Revascularization end points in stroke interventional trials:recanalization versus reperfusion in IMS-I[J]. Stroke, 2005,36(11):2400-3.
[68]Stewart, D.J., J.M. Belanger, Z. Grahovac, et al. Phase I study of intracarotid administration of carboplatin[J]. N euro surgery,1992,30(4):512-6; discussion 516-7.
[1]Hacke, W., S. Schwab, M. Horn, et al.'Malignant'middle cerebral artery territory infarction:clinical course and prognostic signs[J]. Arch Neurol,1996, 53(4):309-15.
[2]Huttner, H.B.,S. Schwab. Malignant middle cerebral artery infarction:clinical characteristics, treatment strategies, and future perspectives[J]. Lancet Neurol, 2009,8(10):949-58.
[3]Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group[J]. N Engl J Med,1995,333(24):1581-7.
[4]Hofmeijer, J., L.J. Kappelle, A. Algra, et al. Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]):a multicentre, open, randomised trial[J]. Lancet Neurol,2009,8(4):326-33.
[5]Hara, M.R.,S.H. Snyder. Cell signaling and neuronal death[J]. Annu Rev Pharmacol Toxicol,2007,47:117-41.
[6]Doyle, K.P., R.P. Simon,M.P. Stenzel-Poore. Mechanisms of ischemic brain damage[J]. Neuropharmacology,2008,55(3):310-8.
[7]Nedergaard, M. Mechanisms of brain damage in focal cerebral ischemia[J]. Acta Neurol Scand,1988,77(2):81-101.
[8]Linares, G.,S.A. Mayer. Hypothermia for the treatment of ischemic and hemorrhagic stroke[J]. Crit Care Med,2009,37(7 Suppl):S243-9.
[9]Hoesch, R.E.,R.G. Geocadin. Therapeutic hypothermia for global and focal ischemic brain injury--a cool way to improve neurologic outcomes[J]. Neurologist,2007,13(6):331-42.
[10]Jiang, J.Y., W. Xu, P.F. Yang, et al. Marked protection by selective cerebral profound hypothermia after complete cerebral ischemia in primates[J]. J Neurotrauma,2006,23(12):1847-56.
[11]Kollmar, R.,S. Schwab. Hypothermia and Ischemic Stroke[J]. Curr Treat Options Neurol,2012.
[12]Faridar, A., E.M. Bershad, T. Emiru, et al. Therapeutic hypothermia in stroke and traumatic brain injury[J]. Front Neurol,2011,2:80.
[13]Zeiner, A., M. Holzer, F. Sterz, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group[J]. Stroke,2000, 31(1):86-94.
[14]Kader, A., M.H. Brisman, N. Maraire, et al. The effect of mild hypothermia on permanent focal ischemia in the rat[J]. Neurosurgery,1992,31(6):1056-60; discussion 1060-1.
[15]Maier, C.M., K. Ahern, M.L. Cheng, et al. Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia:effects on neurologic outcome, infarct size, apoptosis, and inflammation[J]. Stroke,1998, 29(10):2171-80.
[16]Huh, P.W., L. Belayev, W. Zhao, et al. Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia[J]. J Neurosurg,2000,92(1):91-9.
[17]Karibe, H., J. Chen, G.J. Zarow, et al. Delayed induction of mild hypothermia to reduce infarct volume after temporary middle cerebral artery occlusion in rats[J]. J Neurosurg,1994,80(1):112-9.
[18]Baker, C.J., S.T. Onesti,R.A. Solomon. Reduction by delayed hypothermia of cerebral infarction following middle cerebral artery occlusion in the rat:a time-course study[J]. J Neurosurg,1992,77(3):438-44.
[19]Markarian, G.Z., J.H. Lee, D.J. Stein, et al. Mild hypothermia:therapeutic window after experimental cerebral ischemia[J]. Neurosurgery,1996,38(3): 542-50; discussion 551.
[20]Colbourne, F., D. Corbett, Z. Zhao, et al. Prolonged but delayed postischemic hypothermia:a long-term outcome study in the rat middle cerebral artery occlusion model[J]. J Cereb Blood Flow Metab,2000,20(12):1702-8.
[21]Maier, C.M., G.H. Sun, D. Kunis, et al. Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size[J]. J Neurosurg,2001,94(1):90-6.
[22]Krieger, D.W.,M.A. Yenari. Therapeutic hypothermia for acute ischemic stroke:what do laboratory studies teach us?[J]. Stroke,2004,35(6):1482-9.
[23]Zhang, Z.G., M. Chopp,H. Chen. Duration dependent post-ischemic hypothermia alleviates cortical damage after transient middle cerebral artery occlusion in the rat[J]. J Neurol Sci,1993,117(1-2):240-4.
[24]Colbourne, F., H. Li,A.M. Buchan. Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats[J]. J Cereb Blood Flow Metab,1999,19(7):742-9.
[25]Rivera-Lara, L., J. Zhang,S. Muehlschlegel. Therapeutic Hypothermia for Acute Neurological Injuries[J]. Neurotherapeutics,2011.
[26]Auriel, E.,N.M. Bornstein. Neuroprotection in acute ischemic stroke--current status[J]. J Cell Mol Med,14(9):2200-2.
[27]Tang, X.N., L. Liu,M.A. Yenari. Combination therapy with hypothermia for treatment of cerebral ischemia[J]. J Neurotrauma,2009,26(3):325-31.
[28]Hemmen, T.M.,P.D. Lyden. Multimodal neuroprotective therapy with induced hypothermia after ischemic stroke[J]. Stroke,2009,40(3 Suppl):S126-8.
[29]Nito, C., T. Kamiya, M. Ueda, et al. Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats[J]. Brain Res,2004,1008(2): 179-85.
[30]Coimbra, C., M. Drake, F. Boris-Moller, et al. Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia[J]. Stroke,1996,27(9):1578-85.
[31]Chen, J., X. Ji, Y. Ding, et al. A novel approach to reduce hemorrhagic transformation after interventional management of acute stroke: catheter-based selective hypothermia[J]. Med Hypotheses,2009,72(1):62-3.
[32]Ding, Y., J. Li, X. Luan, et al. Local saline infusion into ischemic territory induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion[J]. Neurosurgery,2004,54(4):956-64; discussion 964-5.
[33]Ding, Y., C.N. Young, J. Li, et al. Reduced inflammatory mediator expression by pre-reperfusion infusion into ischemic territory in rats:a real-time polymerase chain reaction analysis[J]. Neurosci Lett,2003,353(3):173-6.
[34]Ding, Y., J. Li, J.A. Rafols, et al. Prereperfusion saline infusion into ischemic territory reduces inflammatory injury after transient middle cerebral artery occlusion in rats[J]. Stroke,2002,33(10):2492-8.
[35]Neimark, M.A., A.A. Konstas, J.H. Choi, et al. Brain cooling maintenance with cooling cap following induction with intracarotid cold saline infusion:a quantitative model[J]. J Theor Biol,2008,253(2):333-44.
[36]Cotton, D.B., M. Hallak, C. Janusz, et al. Central anticonvulsant effects of magnesium sulfate on N-methyl-D-aspartate-induced seizures[J]. Am J Obstet Gynecol,1993,168(3 Pt 1):974-8.
[37]Kinoshita, Y., T. Ueyama, E. Senba, et al. Expression of c-fos, heat shock protein 70, neurotrophins, and cyclooxygenase-2 mRNA in response to focal cerebral ischemia/reperfusion in rats and their modification by magnesium sulfate[J]. J Neurotrauma,2001,18(4):435-45.
[38]Lin, J.Y., S.Y. Chung, M.C. Lin, et al. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique[J]. Life Sci,2002,71(7):803-11.
[39]Muir, K.W. Magnesium for neuroprotection in ischaemic stroke:rationale for use and evidence of effectiveness [J]. CNS Drugs,2001,15(12):921-30.
[40]Marinov, M.B., K.S. Harbaugh, P.J. Hoopes, et al. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia[J]. J Neurosurg,1996,85(1):117-24.
[41]Lee, E.J., M.Y. Lee, G.L. Chang, et al. Delayed treatment with magnesium: reduction of brain infarction and improvement of electrophysiological recovery following transient focal cerebral ischemia in rats[J]. J Neurosurg, 2005,102(6):1085-93.
[42]Campbell, K., B.P. Meloni,N.W. Knuckey. Combined magnesium and mild hypothermia (35 degrees C) treatment reduces infarct volumes after permanent middle cerebral artery occlusion in the rat at 2 and 4, but not 6 h[J]. Brain Res,2008,1230:258-64.
[43]Zhu, H., B.P. Meloni, C. Bojarski, et al. Post-ischemic modest hypothermia (35 degrees C) combined with intravenous magnesium is more effective at reducing CA1 neuronal death than either treatment used alone following global cerebral ischemia in rats[J]. Exp Neurol,2005,193(2):361-8.
[44]Schwartz, A.E., J.G. Stone, A.D. Finck, et al. Isolated cerebral hypothermia by single carotid artery perfusion of extracorporeally cooled blood in baboons[J]. Neurosurgery,1996,39(3):577-81; discussion 581-2.
[45]Nishi, H., T. Watanabe, H. Sakurai, et al. Effect of MCI-186 on brain edema in rats[J]. Stroke,1989,20(9):1236-40.
[46]Rother, J. Neuroprotection does not work! [J]. Stroke,2008,39(2):523-4.
[47]O'Collins, V.E., M.R. Macleod, G.A. Donnan, et al. Evaluation of combination therapy in animal models of cerebral ischemia[J]. J Cereb Blood Flow Metab, 2012.
[48]Liniger, R., R. Popovic, B. Sullivan, et al. Effects of neuroprotective cocktails on hippocampal neuron death in an in vitro model of cerebral ischemia[J]. J Neurosurg Anesthesiol,2001,13(1):19-25.
[49]Aronowski, J., R. Strong, A. Shirzadi, et al. Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke:preclinical experience [J]. Stroke,2003,34(5): 1246-51.
[50]Berger, C., W.R. Schabitz, M. Wolf, et al. Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke [J]. Exp Neurol,2004,185(2):305-12.
[51]Zhao, H., M.A. Yenari, R.M. Sapolsky, et al. Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome C release[J]. Stroke,2004,35(2):572-7.
[52]Berrouschot, J., M. Sterker, S. Bettin, et al. Mortality of space-occupying ('malignant') middle cerebral artery infarction under conservative intensive care[J]. Intensive Care Med,1998,24(6):620-3.
[53]Hamann, G.F., Y. Okada, R. Fitridge, et al. Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion[J]. Stroke,1995, 26(11):2120-6.
[54]Rosenberg, G.A., L.A. Cunningham, J. Wallace, et al. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain:activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures[J]. Brain Res, 2001,893(1-2):104-12.
[55]Fujimura, M., Y. Gasche, Y. Morita-Fujimura, et al. Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion [J]. Brain Res,1999,842(1): 92-100.
[56]Rosenberg, G.A., E.Y. Estrada,J.E. Dencoff. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain[J]. Stroke,1998,29(10):2189-95.
[57]Crocker, S.J., A. Pagenstecher,I.L. Campbell. The TIMPs tango with MMPs and more in the central nervous system[J]. J Neurosci Res,2004,75(1):1-11.
[58]Asahi, M., X. Wang, T. Mori, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia[J]. J Neurosci,2001,21(19):7724-32.
[59]Asahi, M., K. Asahi, J.C. Jung, et al. Role for matrix metalloproteinase 9 after focal cerebral ischemia:effects of gene knockout and enzyme inhibition with BB-94[J]. J Cereb Blood Flow Metab,2000,20(12):1681-9.
[60]Carrera, R.M., A.M. Pacheco, Jr.,R.A. Mastroti. Qualitative evaluation of the blood-brain barrier after the use of hypertonic saline solution in young rats[J]. Eur Surg Res,2001,33(5-6):311-7.
[2]Bernard, S.A., T.W. Gray, M.D. Buist, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia[J]. N Engl J Med, 2002,346(8):557-63.
[3]Zeiner, A., M. Holzer, F. Sterz, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group[J]. Stroke,2000, 31(1):86-94.
[4]Moran, J.L.,P.J. Solomon. Application of therapeutic hypothermia in the intensive care unit[J]. Intensive Care Med,2004,30(12):2288; author reply 2287.
[5]Fay. Observations on generalized refrigeration in cases of severe cerebral trauma[J]. Assoc Res Nerv Ment Dis Proc,1943,24:611-619.
[6]Ravitch, M.M., R. Lane, P. Safar, et al. Lightning stroke. Report of a case with recovery after cardiac massage and prolonged artificial respiration[J]. N Engl J Med,1961,264:36-8.
[7]Weinrauch, V., P. Safar, S. Tisherman, et al. Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs[J]. Stroke,1992,23(10):1454-62.
[8]Gunn, A.J.,M. Thoresen. Hypothermic neuroprotection[J]. NeuroRx,2006, 3(2):154-69.
[9]Zhang, Y., K.C. Wong,Z. Zhang. The effect of intraischemic mild hypothermia on focal cerebral ischemia/reperfusion injury[J]. Acta Anaesthesiol Sin,2001, 39(2):65-9.
[10]Hoffman, P.J., D.B. Milliken, L.C. Gregg, et al. Molecular characterization of uterine fibroids and its implication for underlying mechanisms of pathogenesis[J]. Fertil Steril,2004,82(3):639-49.
[11]Busto, R., M.Y. Globus, W.D. Dietrich, et al. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain[J]. Stroke,1989,20(7):904-10.
[12]Baker, C.J., A.J. Fiore, V.I. Frazzini, et al. Intraischemic hypothermia decreases the release of glutamate in the cores of permanent focal cerebral infarcts[J]. Neurosurgery,1995,36(5):994-1001; discussion 1001-2.
[13]Phanithi, P.B., Y. Yoshida, A. Santana, et al. Mild hypothermia mitigates post-ischemic neuronal death following focal cerebral ischemia in rat brain: immunohistochemical study of Fas, caspase-3 and TUNEL[J]. Neuropathology,2000,20(4):273-82.
[14]Niwa, M., A. Hara, T. Iwai, et al. Relationship between magnitude of hypothermia during ischemia and preventive effect against post-ischemic DNA fragmentation in the gerbil hippocampus[J]. Brain Res,1998,794(2): 338-42.
[15]Reuler, J.B. Hypothermia:pathophysiology, clinical settings, and management[J]. Ann Intern Med,1978,89(4):519-27.
[16]Frank, S.M., L.A. Fleisher, M.J. Breslow, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial[J]. JAMA,1997,277(14):1127-34.
[17]Schmied, H., A. Schiferer, D.I. Sessler, et al. The effects of red-cell scavenging, hemodilution, and active warming on allogenic blood requirements in patients undergoing hip or knee arthroplasty[J]. Anesth Analg, 1998,86(2):387-91.
[18]Sessler, D.I., C.I. Olofsson,E.H. Rubinstein. The thermoregulatory threshold in humans during nitrous oxide-fentanyl anesthesia[J]. Anesthesiology,1988, 69(3):357-64.
[19]Wenisch, C., E. Narzt, D.I. Sessler, et al. Mild intraoperative hypothermia reduces production of reactive oxygen intermediates by polymorphonuclear leukocytes[J]. Anesth Analg,1996,82(4):810-6.
[20]Gadkary, C.S., P. Alderson,D.F. Signorini. Therapeutic hypothermia for head injury[J]. Cochrane Database Syst Rev,2002(1):CD001048.
[21]Kurz, A., D.I. Sessler,R. Lenhardt. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group[J]. N Engl J Med,1996,334(19): 1209-15.
[22]Morgan, D.B.,R.M. Young. Acute transient hypokalaemia:new interpretation of a common event [J]. Lancet,1982,2(8301):751-2.
[23]Koht, A., R. Cane,L.J. Cerullo. Serum potassium levels during prolonged hypothermia[J]. Intensive Care Med,1983,9(5):275-7.
[24]Bloch, M. Cerebral effects of rewarming following prolonged hypothermia: significance for the management of severe cranio-cerebral injury and acute pyrexia[J]. Brain,1967,90(4):769-84.
[25]Schwab, S., S. Schwarz, M. Spranger, et al. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction [J]. Stroke, 1998,29(12):2461-6.
[26]Schwab, S., D. Georgiadis, J. Berrouschot, et al. Feasibility and safety of moderate hypothermia after massive hemispheric infarction[J]. Stroke,2001, 32(9):2033-5.
[27]Maloney, S.K., A. Fuller, G. Mitchell, et al. Rectal temperature measurement results in artifactual evidence of selective brain cooling[J]. Am J Physiol Regul Integr Comp Physiol,2001,281(1):R108-14.
[28]Wang, H., W. Olivero, G. Lanzino, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet[J]. J Neurosurg,2004,100(2): 272-7.
[29]Qiu, W., H. Shen, Y. Zhang, et al. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury[J]. J Clin Neurosci,2006,13(10):995-1000.
[30]Abou-Chebl, A., M.A. DeGeorgia, J.C. Andrefsky, et al. Technical refinements and drawbacks of a surface cooling technique for the treatment of severe acute ischemic stroke[J]. Neurocrit Care,2004,1(2):131-43.
[31]Corbett, R.J.,A.R. Laptook. Failure of localized head cooling to reduce brain temperature in adult humans[J]. Neuroreport,1998,9(12):2721-5.
[32]Neimark, M.A., A.A. Konstas, J.H. Choi, et al. Local control of temperature in a theoretical human model of selective brain cooling[J]. Conf Proc IEEE Eng Med Biol Soc,2007,2007:6349-52.
[33]Cheng, H., J. Shi, L. Zhang, et al. Epidural cooling for selective brain hypothermia in porcine model[J]. Acta Neurochir (Wien),2006,148(5): 559-64; discussion 564.
[34]Parkins, W.M., J.M. Jensen,H.M. Vars. Brain cooling in the prevention of brain damage during periods of circulatory occlusion in dogs[J]. Ann Surg, 1954,140(3):284-9.
[35]Ohta, T., I. Sakaguchi, L.W. Dong, et al. Selective cooling of brain using profound hemodilution in dogs[J]. Neurosurgery,1992,31(6):1049-54; discussion 1054-5.
[36]Schwartz, A.E., J.G. Stone, A.D. Finck, et al. Isolated cerebral hypothermia by single carotid artery perfusion of extracorporeally cooled blood in baboons[J]. Neurosurgery,1996,39(3):577-81; discussion 581-2.
[37]Jiang, J.Y., W. Xu, P.F. Yang, et al. Marked protection by selective cerebral profound hypothermia after complete cerebral ischemia in primates[J]. J Neurotrauma,2006,23(12):1847-56.
[38]Wen, Y.S., M.S. Huang, M.T. Lin, et al. Rapid brain cooling by hypothermic retrograde jugular vein flush[J]. J Trauma,2005,58(3):577-81.
[39]Neimark, M.A., A.A. Konstas, J.H. Choi, et al. The role of intracarotid cold saline infusion on a theoretical brain model incorporating the circle of willis and cerebral venous return[J]. Conf Proc IEEE Eng Med Biol Soc,2007,2007: 1140-3.
[40]Slotboom, J., C. Kiefer, C. Brekenfeld, et al. Locally induced hypothermia for treatment of acute ischaemic stroke:a physical feasibility study [J]. Neuroradiology,2004,46(11):923-34.
[41]Choi, J.H., R.S. Marshall, M.A. Neimark, et al. Selective brain cooling with endovascular intracarotid infusion of cold saline:a pilot feasibility study [J]. AJNR Am J Neuroradiol,2010,31(5):928-34.
[42]Ding, Y., J. Li, X. Luan, et al. Local saline infusion into ischemic territory induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion[J]. Neurosurgery,2004,54(4):956-64; discussion 964-5.
[43]Ding, Y, J. Li, Q. Lai, et al. Motor balance and coordination training enhances functional outcome in rat with transient middle cerebral artery occlusion[J]. Neuroscience,2004,123(3):667-74.
[44]Toung, T.J., A. Bhardwaj, V.L. Dawson, et al. Neuroprotective FK506 does not alter in vivo nitric oxide production during ischemia and early reperfusion in rats[J]. Stroke,1999,30(6):1279-85.
[45]Rusa, R., N.J. Alkayed, B.J. Crain, et al.17beta-estradiol reduces stroke injury in estrogen-deficient female animals[J]. Stroke,1999,30(8):1665-70.
[46]Schabitz, W.R., C. Berger, R. Kollmar, et al. Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia[J]. Stroke,2004,35(4):992-7.
[47]Nishi, H., T. Watanabe, H. Sakurai, et al. Effect of MCI-186 on brain edema in rats[J]. Stroke,1989,20(9):1236-40.
[1]Vande Linde, A.M., M. Chopp, H. Chen, et al. Chronic changes in the brain Mg2+concentration after forebrain ischemia in the rat[J]. Metab Brain Dis, 1991,6(4):199-206.
[2]Vink, R., D.L. Heath,T.K. McIntosh. Acute and prolonged alterations in brain free magnesium following fluid percussion-induced brain trauma in rats[J]. J Neurochem,1996,66(6):2477-83.
[3]Lee, M.S., Y.S. Wu, D.Y. Yang, et al. Significantly decreased extracellular magnesium in brains of gerbils subjected to cerebral ischemia[J]. Clin Chim Acta,2002,318(1-2):121-5.
[4]Muir, J.K., R. Raghupathi, D.L. Emery, et al. Postinjury magnesium treatment attenuates traumatic brain injury-induced cortical induction of p53 mRNA in rats[J]. Exp Neurol,1999,159(2):584-93.
[5]van den Bergh, W.M., J.K. Zuur, N.A. Kamerling, et al. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage[J]. J Neurosurg,2002,97(2):416-22.
[6]Muir, K.W. Magnesium for neuroprotection in ischaemic stroke:rationale for use and evidence of effectiveness [J]. CNS Drugs,2001,15(12):921-30.
[7]van den Bergh, W.M., A. Algra, F. van Kooten, et al. Magnesium sulfate in aneurysmal subarachnoid hemorrhage:a randomized controlled trial[J]. Stroke, 2005,36(5):1011-5.
[8]Grubbs, R.D.,M.E. Maguire. Magnesium as a regulatory cation:criteria and evaluation[J]. Magnesium,1987,6(3):113-27.
[9]Nowak, L., P. Bregestovski, P. Ascher, et al. Magnesium gates glutamate-activated channels in mouse central neurones[J]. Nature,1984, 307(5950):462-5.
[10]Cotton, D.B., M. Hallak, C. Janusz, et al. Central anticonvulsant effects of magnesium sulfate on N-methyl-D-aspartate-induced seizures[J]. Am J Obstet Gynecol,1993,168(3 Pt 1):974-8.
[11]Kaya, M., S. Gulturk, I. Elmas, et al. The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats[J]. Life Sci,2004,76(2):201-12.
[12]Chi, O.Z., P. Pollak,H.R. Weiss. Effects of magnesium sulfate and nifedipine on regional cerebral blood flow during middle cerebral artery ligation in the rat[J]. Arch Int Pharmacodyn Ther,1990,304:196-205.
[13]Kemp, P.A., S.M. Gardiner, T. Bennett, et al. Magnesium sulphate reverses the carotid vasoconstriction caused by endothelin-Ⅰ, angiotensin Ⅱ and neuropeptide-Y, but not that caused by NG-nitro-L-arginine methyl ester, in conscious rats[J]. Clin Sci (Lond),1993,85(2):175-81.
[14]Izumi, Y., S. Roussel, E. Pinard, et al. Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats[J]. J Cereb Blood Flow Metab,1991,11(6):1025-30.
[15]Schmid-Elsaesser, R., S. Zausinger, E. Hungerhuber, et al. Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia[J]. Neurosurgery,1999,44(1):163-71; discussion 171-2.
[16]Yang, Y, Q. Li, F. Ahmad, et al. Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat[J]. Neurosci Lett,2000,285(2):119-22.
[17]Kinoshita, Y, T. Ueyama, E. Senba, et al. Expression of c-fos, heat shock protein 70, neurotrophins, and cyclooxygenase-2 mRNA in response to focal cerebral ischemia/reperfusion in rats and their modification by magnesium sulfate[J]. J Neurotrauma,2001,18(4):435-45.
[18]Lin, J.Y., S.Y. Chung, M.C. Lin, et al. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique[J]. Life Sci,2002,71(7):803-11.
[19]Zhu, H.D., R. Martin, B. Meloni, et al. Magnesium sulfate fails to reduce infarct volume following transient focal cerebral ischemia in rats[J]. Neurosci Res,2004,49(3):347-53.
[20]Westermaier, T., S. Zausinger, A. Baethmann, et al. Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats[J]. Acta Neurochir (Wien),2005,147(5):525-32; discussion 532.
[21]Marinov, M.B., K.S. Harbaugh, P.J. Hoopes, et al. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia[J]. J Neurosurg,1996,85(1):117-24.
[22]Lee, E.J., M.Y. Lee, G.L. Chang, et al. Delayed treatment with magnesium: reduction of brain infarction and improvement of electrophysiological recovery following transient focal cerebral ischemia in rats[J]. J Neurosurg, 2005,102(6):1085-93.
[23]Johansson, B.W. Magnesium infusion in decompensated hypomagnesemic patients[J]. Acta Pharmacol Toxicol (Copenh),1984,54 Suppl 1:125-8.
[24]Muir, K.W., K.R. Lees, I. Ford, et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial):randomised controlled trial [J]. Lancet, 2004,363(9407):439-45.
[25]Muir, K.W.,K.R. Lees. Dose optimization of intravenous magnesium sulfate after acute stroke[J]. Stroke,1998,29(5):918-23.
[26]Lampl, Y., R. Gilad, D. Geva, et al. Intravenous administration of magnesium sulfate in acute stroke:a randomized double-blind study [J]. Clin Neuropharmacol,2001,24(1):11-5.
[27]Aslanyan, S., C.J. Weir, K.W. Muir, et al. Magnesium for treatment of acute lacunar stroke syndromes:further analysis of the IMAGES trial[J]. Stroke, 2007,38(4):1269-73.
[28]Saver, J.L., C. Kidwell, M. Eckstein, et al. Prehospital neuroprotective therapy for acute stroke:results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial[J]. Stroke,2004,35(5):e106-8.
[29]Meloni, B.P., H. Zhu,N.W. Knuckey. Is magnesium neuroprotective following global and focal cerebral ischaemia? A review of published studies[J]. Magnes Res,2006,19(2):123-37.
[30]Rother, J. Neuroprotection does not work![J]. Stroke,2008,39(2):523-4.
[31]Joshi, S., P.M. Meyers,E. Ornstein. Intracarotid delivery of drugs:the potential and the pitfalls[J]. Anesthesiology,2008,109(3):543-64.
[32]Bazin, J.E., P. Picard, J. Gabrillargues, et al. Propofol administered via the carotid artery to achieve a Wada test[J]. Can J Anaesth,1998,45(7):707-8.
[33]Uemura, S., Y. Matsukado, S. Yoshioka, et al. [Prevention of ocular toxicity by the intra-carotid perfusion of anticancer agents in the treatment of malignant glioma. Usefulness of a remodeled epidural catheter and selective CT enhancements][J]. Neurol Med Chir (Tokyo),1986,26(6):461-7.
[34]Myklebust, A.T., A. Helseth, K. Breistol, et al. Nude rat models for human tumor metastasis to CNS. Procedures for intracarotid delivery of cancer cells and drugs[J]. J Neurooncol,1994,21(3):215-24.
[35]Jahan, R. Hyperacute therapy of acute ischemic stroke:intraarterial thrombolysis and mechanical revascularization strategies [J]. Tech Vase Interv Radiol,2005,8(2):87-91.
[36]Taussky, P., R.G. Tawk, W.P. Daugherty, et al. Medical therapy for ischemic stroke:review of intravenous and intra-arterial treatment options[J]. World Neurosurg,76(6 Suppl):S9-15.
[37]Nishi, H., T. Watanabe, H. Sakurai, et al. Effect of MCI-186 on brain edema in rats[J]. Stroke,1989,20(9):1236-40.
[38]Kermer, P., N. Klocker,M. Bahr. Neuronal death after brain injury. Models, mechanisms, and therapeutic strategies in vivo[J]. Cell Tissue Res,1999, 298(3):383-95.
[39]Johnson, J.W.,P. Ascher. Voltage-dependent block by intracellular Mg2+of N-methyl-D-aspartate-activated channels[J]. Biophys J,1990,57(5):1085-90.
[40]Budd, S.L. Mechanisms of neuronal damage in brain hypoxia/ischemia:focus on the role of mitochondrial calcium accumulation[J]. Pharmacol Ther,1998, 80(2):203-29.
[41]Frandsen, A., A. Schousboe. Effect of magnesium on NMD A mediated toxicity and increases in [Ca2+]i and cGMP in cultured neocortical neurons:evidence for distinct regulation of different responses[J]. Neurochem Int,1994,25(4): 301-8.
[42]Iseri, L.T.,J.H. French. Magnesium:nature's physiologic calcium blocker[J]. Am Heart J,1984,108(1):188-93.
[43]Kemp, P.A., S.M. Gardiner, J.E. March, et al. Assessment of the effects of endothelin-1 and magnesium sulphate on regional blood flows in conscious rats, by the coloured microsphere reference technique[J]. Br J Pharmacol, 1999,126(3):621-6.
[44]Aisenbrey, G.A., E. Corwin,V. Catanzarite. Effect of magnesium sulfate on the vascular actions of norepinephrine and angiotensin II[J]. Am J Perinatol,1992, 9(5-6):477-80.
[45]Torregrosa, G, A.J. Perales, J.B. Salom, et al. Different effects of Mg2+on endothelin-1-and 5-hydroxytryptamine-elicited responses in goat cerebrovascular bed[J]. J Cardiovasc Pharmacol,1994,23(6):1004-10.
[46]Ram, Z., M. Sadeh, I. Shacked, et al. Magnesium sulfate reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in rats[J]. Stroke,1991,22(7):922-7.
[47]Perales, A.J., G. Torregrosa, J.B. Salom, et al. In vivo and in vitro effects of magnesium sulfate in the cerebrovascular bed of the goat[J]. Am J Obstet Gynecol,1991,165(5 Pt 1):1534-8.
[48]Alborch, E., J.B. Salom, A.J. Perales, et al. Comparison of the anticonstrictor action of dihydropyridines (nimodipine and nicardipine) and Mg2+in isolated human cerebral arteries[J]. Eur J Pharmacol,1992,229(1):83-9.
[49]Adams, J.H.,J.R. Mitchell. The effect of agents which modify platelet behaviour and of magnesium ions on thrombus formation in vivo[J]. Thromb Haemost,1979,42(2):603-10.
[50]Kurgan, A., S.D. Gertz, R.S. Wajnberg, et al. Effect of magnesium sulfate on platelet deposition in rabbits following temporary arterial occlusion with surgical clips[J]. Surgery,1980,87(4):390-6.
[51]Ravn, H.B., H. Vissinger, S.D. Kristensen, et al. Magnesium inhibits platelet activity-an infusion study in healthy volunteers[J]. Thromb Haemost,1996, 75(6):939-44.
[52]Kynczl-Leisure, M.,L.A. Cibils. Increased bleeding time after magnesium sulfate infusion[J]. Am J Obstet Gynecol,1996,175(5):1293-4.
[53]ISIS-4:a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group[J]. Lancet,1995,345(8951):669-85.
[54]Green, A.R.,A. Shuaib. Therapeutic strategies for the treatment of stroke[J]. Drug Discov Today,2006,11(15-16):681-93.
[55]Lees, K.R., J.A. Zivin, T. Ashwood, et al. NXY-059 for acute ischemic stroke[J]. N Engl J Med,2006,354(6):588-600.
[56]Shuaib, A., K.R. Lees, P. Lyden, et al. NXY-059 for the treatment of acute ischemic stroke[J]. N Engl J Med,2007,357(6):562-71.
[57]Use of anti-ICAM-1 therapy in ischemic stroke:results of the Enlimomab Acute Stroke Trial[J]. Neurology,2001,57(8):1428-34.
[58]Wada, J..T. Rasmussen. Intracarotid injection of sodium amytal for the lateralization of cerebral speech dominance.1960[J]. J Neurosurg,2007, 106(6):1117-33.
[59]Dedrick, R.L., E.H. Oldfield,J.M. Collins. Arterial drug infusion with extracorporeal removal. I. Theoretic basis with particular reference to the brain[J]. Cancer Treat Rep,1984,68(2):373-80.
[60]Neuwelt, E.A., M. Pagel, P. Barnett, et al. Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification[J]. Cancer Res,1981,41(11 Pt 1):4466-70.
[61]Joshi, S., C.W. Emala,J. Pile-Spellman. Intra-arterial drug delivery:a concise review[J]. J Neurosurg Anesthesiol,2007,19(2):111-9.
[62]Gobin, Y.P., T.F. Cloughesy, K.L. Chow, et al. Intraarterial chemotherapy for brain tumors by using a spatial dose fractionation algorithm and pulsatile delivery[J]. Radiology,2001,218(3):724-32.
[63]Yamashita, J., H. Handa, Y. Tokuriki, et al. Intra-arterial ACNU therapy for malignant brain tumors. Experimental studies and preliminary clinical results[J]. J Neurosurg,1983,59(3):424-30.
[64]Joshi, S., W.L. Young, J. Pile-Spellman, et al. The feasibility of intracarotid adenosine for the manipulation of human cerebrovascular resistance [J]. Anesth Analg,1998,87(6):1291-8.
[65]Jones, D.R., S.D. Hall, E.K. Jackson, et al. Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding[J]. J Pharmacol Exp Ther, 1988,245(3):816-22.
[66]Joshi, S., M. Wang, J.J. Etu, et al. Bolus configuration affects dose requirements of intracarotid propofol for electroencephalographic silence[J]. Anesth Analg,2006,102(6):1816-22.
[67]Khatri, P., J. Neff, J.P. Broderick, et al. Revascularization end points in stroke interventional trials:recanalization versus reperfusion in IMS-I[J]. Stroke, 2005,36(11):2400-3.
[68]Stewart, D.J., J.M. Belanger, Z. Grahovac, et al. Phase I study of intracarotid administration of carboplatin[J]. N euro surgery,1992,30(4):512-6; discussion 516-7.
[1]Hacke, W., S. Schwab, M. Horn, et al.'Malignant'middle cerebral artery territory infarction:clinical course and prognostic signs[J]. Arch Neurol,1996, 53(4):309-15.
[2]Huttner, H.B.,S. Schwab. Malignant middle cerebral artery infarction:clinical characteristics, treatment strategies, and future perspectives[J]. Lancet Neurol, 2009,8(10):949-58.
[3]Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group[J]. N Engl J Med,1995,333(24):1581-7.
[4]Hofmeijer, J., L.J. Kappelle, A. Algra, et al. Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]):a multicentre, open, randomised trial[J]. Lancet Neurol,2009,8(4):326-33.
[5]Hara, M.R.,S.H. Snyder. Cell signaling and neuronal death[J]. Annu Rev Pharmacol Toxicol,2007,47:117-41.
[6]Doyle, K.P., R.P. Simon,M.P. Stenzel-Poore. Mechanisms of ischemic brain damage[J]. Neuropharmacology,2008,55(3):310-8.
[7]Nedergaard, M. Mechanisms of brain damage in focal cerebral ischemia[J]. Acta Neurol Scand,1988,77(2):81-101.
[8]Linares, G.,S.A. Mayer. Hypothermia for the treatment of ischemic and hemorrhagic stroke[J]. Crit Care Med,2009,37(7 Suppl):S243-9.
[9]Hoesch, R.E.,R.G. Geocadin. Therapeutic hypothermia for global and focal ischemic brain injury--a cool way to improve neurologic outcomes[J]. Neurologist,2007,13(6):331-42.
[10]Jiang, J.Y., W. Xu, P.F. Yang, et al. Marked protection by selective cerebral profound hypothermia after complete cerebral ischemia in primates[J]. J Neurotrauma,2006,23(12):1847-56.
[11]Kollmar, R.,S. Schwab. Hypothermia and Ischemic Stroke[J]. Curr Treat Options Neurol,2012.
[12]Faridar, A., E.M. Bershad, T. Emiru, et al. Therapeutic hypothermia in stroke and traumatic brain injury[J]. Front Neurol,2011,2:80.
[13]Zeiner, A., M. Holzer, F. Sterz, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group[J]. Stroke,2000, 31(1):86-94.
[14]Kader, A., M.H. Brisman, N. Maraire, et al. The effect of mild hypothermia on permanent focal ischemia in the rat[J]. Neurosurgery,1992,31(6):1056-60; discussion 1060-1.
[15]Maier, C.M., K. Ahern, M.L. Cheng, et al. Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia:effects on neurologic outcome, infarct size, apoptosis, and inflammation[J]. Stroke,1998, 29(10):2171-80.
[16]Huh, P.W., L. Belayev, W. Zhao, et al. Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia[J]. J Neurosurg,2000,92(1):91-9.
[17]Karibe, H., J. Chen, G.J. Zarow, et al. Delayed induction of mild hypothermia to reduce infarct volume after temporary middle cerebral artery occlusion in rats[J]. J Neurosurg,1994,80(1):112-9.
[18]Baker, C.J., S.T. Onesti,R.A. Solomon. Reduction by delayed hypothermia of cerebral infarction following middle cerebral artery occlusion in the rat:a time-course study[J]. J Neurosurg,1992,77(3):438-44.
[19]Markarian, G.Z., J.H. Lee, D.J. Stein, et al. Mild hypothermia:therapeutic window after experimental cerebral ischemia[J]. Neurosurgery,1996,38(3): 542-50; discussion 551.
[20]Colbourne, F., D. Corbett, Z. Zhao, et al. Prolonged but delayed postischemic hypothermia:a long-term outcome study in the rat middle cerebral artery occlusion model[J]. J Cereb Blood Flow Metab,2000,20(12):1702-8.
[21]Maier, C.M., G.H. Sun, D. Kunis, et al. Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size[J]. J Neurosurg,2001,94(1):90-6.
[22]Krieger, D.W.,M.A. Yenari. Therapeutic hypothermia for acute ischemic stroke:what do laboratory studies teach us?[J]. Stroke,2004,35(6):1482-9.
[23]Zhang, Z.G., M. Chopp,H. Chen. Duration dependent post-ischemic hypothermia alleviates cortical damage after transient middle cerebral artery occlusion in the rat[J]. J Neurol Sci,1993,117(1-2):240-4.
[24]Colbourne, F., H. Li,A.M. Buchan. Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats[J]. J Cereb Blood Flow Metab,1999,19(7):742-9.
[25]Rivera-Lara, L., J. Zhang,S. Muehlschlegel. Therapeutic Hypothermia for Acute Neurological Injuries[J]. Neurotherapeutics,2011.
[26]Auriel, E.,N.M. Bornstein. Neuroprotection in acute ischemic stroke--current status[J]. J Cell Mol Med,14(9):2200-2.
[27]Tang, X.N., L. Liu,M.A. Yenari. Combination therapy with hypothermia for treatment of cerebral ischemia[J]. J Neurotrauma,2009,26(3):325-31.
[28]Hemmen, T.M.,P.D. Lyden. Multimodal neuroprotective therapy with induced hypothermia after ischemic stroke[J]. Stroke,2009,40(3 Suppl):S126-8.
[29]Nito, C., T. Kamiya, M. Ueda, et al. Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats[J]. Brain Res,2004,1008(2): 179-85.
[30]Coimbra, C., M. Drake, F. Boris-Moller, et al. Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia[J]. Stroke,1996,27(9):1578-85.
[31]Chen, J., X. Ji, Y. Ding, et al. A novel approach to reduce hemorrhagic transformation after interventional management of acute stroke: catheter-based selective hypothermia[J]. Med Hypotheses,2009,72(1):62-3.
[32]Ding, Y., J. Li, X. Luan, et al. Local saline infusion into ischemic territory induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion[J]. Neurosurgery,2004,54(4):956-64; discussion 964-5.
[33]Ding, Y., C.N. Young, J. Li, et al. Reduced inflammatory mediator expression by pre-reperfusion infusion into ischemic territory in rats:a real-time polymerase chain reaction analysis[J]. Neurosci Lett,2003,353(3):173-6.
[34]Ding, Y., J. Li, J.A. Rafols, et al. Prereperfusion saline infusion into ischemic territory reduces inflammatory injury after transient middle cerebral artery occlusion in rats[J]. Stroke,2002,33(10):2492-8.
[35]Neimark, M.A., A.A. Konstas, J.H. Choi, et al. Brain cooling maintenance with cooling cap following induction with intracarotid cold saline infusion:a quantitative model[J]. J Theor Biol,2008,253(2):333-44.
[36]Cotton, D.B., M. Hallak, C. Janusz, et al. Central anticonvulsant effects of magnesium sulfate on N-methyl-D-aspartate-induced seizures[J]. Am J Obstet Gynecol,1993,168(3 Pt 1):974-8.
[37]Kinoshita, Y., T. Ueyama, E. Senba, et al. Expression of c-fos, heat shock protein 70, neurotrophins, and cyclooxygenase-2 mRNA in response to focal cerebral ischemia/reperfusion in rats and their modification by magnesium sulfate[J]. J Neurotrauma,2001,18(4):435-45.
[38]Lin, J.Y., S.Y. Chung, M.C. Lin, et al. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique[J]. Life Sci,2002,71(7):803-11.
[39]Muir, K.W. Magnesium for neuroprotection in ischaemic stroke:rationale for use and evidence of effectiveness [J]. CNS Drugs,2001,15(12):921-30.
[40]Marinov, M.B., K.S. Harbaugh, P.J. Hoopes, et al. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia[J]. J Neurosurg,1996,85(1):117-24.
[41]Lee, E.J., M.Y. Lee, G.L. Chang, et al. Delayed treatment with magnesium: reduction of brain infarction and improvement of electrophysiological recovery following transient focal cerebral ischemia in rats[J]. J Neurosurg, 2005,102(6):1085-93.
[42]Campbell, K., B.P. Meloni,N.W. Knuckey. Combined magnesium and mild hypothermia (35 degrees C) treatment reduces infarct volumes after permanent middle cerebral artery occlusion in the rat at 2 and 4, but not 6 h[J]. Brain Res,2008,1230:258-64.
[43]Zhu, H., B.P. Meloni, C. Bojarski, et al. Post-ischemic modest hypothermia (35 degrees C) combined with intravenous magnesium is more effective at reducing CA1 neuronal death than either treatment used alone following global cerebral ischemia in rats[J]. Exp Neurol,2005,193(2):361-8.
[44]Schwartz, A.E., J.G. Stone, A.D. Finck, et al. Isolated cerebral hypothermia by single carotid artery perfusion of extracorporeally cooled blood in baboons[J]. Neurosurgery,1996,39(3):577-81; discussion 581-2.
[45]Nishi, H., T. Watanabe, H. Sakurai, et al. Effect of MCI-186 on brain edema in rats[J]. Stroke,1989,20(9):1236-40.
[46]Rother, J. Neuroprotection does not work! [J]. Stroke,2008,39(2):523-4.
[47]O'Collins, V.E., M.R. Macleod, G.A. Donnan, et al. Evaluation of combination therapy in animal models of cerebral ischemia[J]. J Cereb Blood Flow Metab, 2012.
[48]Liniger, R., R. Popovic, B. Sullivan, et al. Effects of neuroprotective cocktails on hippocampal neuron death in an in vitro model of cerebral ischemia[J]. J Neurosurg Anesthesiol,2001,13(1):19-25.
[49]Aronowski, J., R. Strong, A. Shirzadi, et al. Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke:preclinical experience [J]. Stroke,2003,34(5): 1246-51.
[50]Berger, C., W.R. Schabitz, M. Wolf, et al. Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke [J]. Exp Neurol,2004,185(2):305-12.
[51]Zhao, H., M.A. Yenari, R.M. Sapolsky, et al. Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome C release[J]. Stroke,2004,35(2):572-7.
[52]Berrouschot, J., M. Sterker, S. Bettin, et al. Mortality of space-occupying ('malignant') middle cerebral artery infarction under conservative intensive care[J]. Intensive Care Med,1998,24(6):620-3.
[53]Hamann, G.F., Y. Okada, R. Fitridge, et al. Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion[J]. Stroke,1995, 26(11):2120-6.
[54]Rosenberg, G.A., L.A. Cunningham, J. Wallace, et al. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain:activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures[J]. Brain Res, 2001,893(1-2):104-12.
[55]Fujimura, M., Y. Gasche, Y. Morita-Fujimura, et al. Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion [J]. Brain Res,1999,842(1): 92-100.
[56]Rosenberg, G.A., E.Y. Estrada,J.E. Dencoff. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain[J]. Stroke,1998,29(10):2189-95.
[57]Crocker, S.J., A. Pagenstecher,I.L. Campbell. The TIMPs tango with MMPs and more in the central nervous system[J]. J Neurosci Res,2004,75(1):1-11.
[58]Asahi, M., X. Wang, T. Mori, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia[J]. J Neurosci,2001,21(19):7724-32.
[59]Asahi, M., K. Asahi, J.C. Jung, et al. Role for matrix metalloproteinase 9 after focal cerebral ischemia:effects of gene knockout and enzyme inhibition with BB-94[J]. J Cereb Blood Flow Metab,2000,20(12):1681-9.
[60]Carrera, R.M., A.M. Pacheco, Jr.,R.A. Mastroti. Qualitative evaluation of the blood-brain barrier after the use of hypertonic saline solution in young rats[J]. Eur Surg Res,2001,33(5-6):311-7.