摘要
目的：再建血运(再灌注)如溶栓治疗是被公认和各国FDA批准的的急性缺血性卒中的唯一治疗手段，但3小时治疗时间窗的限制使多数多病人不能获益。亚低温(28—35℃)是最早在临床实践中被证实有确切疗效的的神经保护手段，而且缺血性脑损伤实验也证实亚低温的神经保护效果是最好的。为此，我们探讨了再灌注期亚低温能否延长再建血运(再灌注)治疗时间窗及其机制，并探讨再灌注期亚低温的脑保护机制。
方法：1将120只SD雄性大鼠随机分为假手术组、大脑中动脉完全闭塞24小时组(MCAO24h组)、常温组：按再灌注时间点不同分为以下亚组：大脑中动脉闭塞2小时、3小时、4小时、5小时、6小时／灌注24小时组(MCAO2h再灌注组、MCAO3h再灌注组、MCAO4h再灌注组、MCAO5h再灌注组、MCAO6h再灌注组)；亚低温组：按再灌注时间点不同分成与常温组对应的亚组。2实施亚低温时将大鼠放入冰屋内，调整冰屋内冰袋数量，使大鼠肛温维持在31士1℃，5h时后，将大鼠移至室内环境复温。亚低温在大脑中动脉再通后即刻实施并持续5小时。线拴法制备大鼠大脑中动脉缺血／再灌注模型。3采用免疫组化法检测大鼠缺血／再灌注模型的AIF、Cyt C、HSP70和MMP-9、LN的表达，并进行TTC染色观察梗死体积，用干-湿重法测定脑含水量，对大鼠模型进行Longa评分。
结果：一再灌注期亚低温与再建血运(再灌注)治疗时间窗的关系及其脑保护的研究结果
1、与脑梗死的近期结局MCAO24h组的梗死体积、Longa评分比较：常温组MCAO2—4h再灌注各组有显著性差异(P＜0．01)，MCAO5—6h再灌注各组没有显著性差异(P＞0．05)；亚低温组MCAO2—5h再灌注各组有显著性差异(P＜0．01)；MCAO6h再灌注各组没有显著性差异(P＞0．05)
2亚低温各组的梗死体积、Longa评分和含水量均显著低于相应常温组(MCAO2-5h各组P＜0．01，MCAO6h组P＜0．05)。
二、再灌注期亚低温延长再建血运(再灌注)治疗时间窗及其脑保护机制的研究结果
1细胞凋亡角度研究的结果
1．1缺血／再灌注各组(常温组、亚低温组)的AIF、Cyt C、HSP70均显著高于假手术组(P＜0．01)。
1．2亚低温各组的AIF、Cyt C均显著低于相应常温组，而HSP70各组阳性细胞计数均显著高于相应常温组(MCAO2-5h各组P＜0．01，MCAO6h组P＜0．05)。
1．3与脑梗死近期结局MCAO24h组的AIF、Cyt C、HSP70：常温组MCAO2—4h再灌注组有显著性差异(P＜0．01)，MCAO5-6h再灌注组无显著性差异(P＞0．05)；亚低温组MCAO2-5h再灌注各组有显著性差异(P＜0．01)；MCAO6h再灌注组无显著性差异(P＞0．05)。
2．血管通透性角度研究的结果
2．1缺血／再灌注各组(常温组、亚低温组)的MMP-9的表达与层粘连蛋白表达呈显著负相关(r=-0．817，P＜0．01)。
2．2再灌注各组(常温组、亚低温组)的MMP-9显著高于假手术组(P＜0．01)；层粘连蛋白显著低于假手术组(P＜0．01)。
2．3亚低温各组的MMP-9均显著低于相应常温组，而层粘连蛋白MCAo2-6h各组阳性细胞计数均显著高于相应常温组(MCAO2-5h各组P＜0．01，MCAO6h组P＜0．05)。
2．4与脑梗死近期结局MCAO24h的MMP-9、层粘连蛋比较：常温组MCAO2-4h再灌注组有显著性差异(P＜0．01)，MCAO5-6h再灌注组无显著性差异(P＞0．05)；亚低温组MCAO2-5h再灌注组有显著性差异(P＜0．01)；MCAO6h再灌注组无显著性差异(P＞0．05)。
结论：1．再灌注期亚低温可延长再建血运(再灌注)治疗的时间窗，通过发挥再灌注期亚低温的脑保护作用(通过同时抑制非caspase和caspase两种凋亡途径，提高HSP70的表达，以全面抑制半暗带细胞的凋亡；对MMP-9的有效抑制使脑微循环破坏减轻，微循环承受再灌注能力上升。)，实现延长治疗时间窗的目的。
2．再灌注期亚低温是一项理想的延长再建血运(再灌注)治疗时间窗的手段：它从抑制半暗带细胞的凋亡和减轻脑血管损伤提高微循环承受再灌注能力等多个角度阻断或减缓缺血／再灌注后的恶性病理生理进程，全面保护缺血／再灌注的脑组织，延长时间窗的效果明显。而其它延长时间窗的治疗手段，作用机制单一，针对性较差(一般不直接针对缺血／再灌注的病理生理)，效果较弱；特别是临床实际上，病人就诊时不可能提前给予亚低温治疗，错过治疗时间窗的病人较多等因素，应用再灌注期亚低温以延长时间窗的临床实用性较大，并且亚低温基础研究和临床使用的手段已经比较成熟，推广起来比较容易。同时由于再灌注期亚低温具有全面的脑保护作用且实用方便，它与其它神经保护剂及各种血管再通手段的联合应用以治疗急性期脑缺血必将有着良好的研究应用前景。
Objective:The most effective treatment for acute ischemic stroke is the early re--storation of blood flow.(reperfusion therapy)to salvage the ischemic penumbrae,thefunc--tionally impaired yet still viable brain tissue,thereby improving clinical outco--me.,but many patient can not benefit from it due to the narrow treatmemt windowtime of 3 h--ours.Hypothermia has been suggested to be the only potent cerebrop--rotection appro--ach in clinic and also been proved to be the best cerebroprotectionapproach.thus,we study whether mild hypothermia (28-35℃)applied during rep--erfusion can prolong the time window ofrestorationofblood (reperfusion)andmechanisms of that and study it's neuroprotection mechanism.
Methods:Methods:1.The adult rats were randomly divided into sham-operationgroup,MCAO24h,NT and HT respectively further divided into 6 subgroups(subjected ischemia for2,3,4,5and6h respectively and then all reperfused for 24h);
2.the rats of hypothermia therapy is immediately loaded into ice-room.changingthe number of ice bags to keep natal temperatures by 31℃±10C.After 5hours,make them rewarm in the room Brain mild hypothermiawas achieved 5hoursimmediately after reperfusion period.The cerebral ischemia/reperfusion model of ratswere achieved by middle cerebral artery occlusion.
3.The expressions ofAIF CytC HSP70and MMP-9 LN were detected byimmunohistochemistry.The infarct volumes were evaluated by TTC staining.Theneurological deficit score were measure by Longa.The water content of rats braintissue were measured by using dry-wet weight method.
Result:The relationship between mild hypothermia applied during reperfusion withthe treatment time window of restoration of blood (reperfusion)and it's protectionduring ischemia/reperfusion.
1.Compared with MCAO24h group in term of the infarction volume and score ofLonga:MCAO2-4h reperfusion groups of NT have significant difference (P＜0.01),MCAO5-6h groups reperfusion of NT have not significant difference (P＞0.05);MCAO2-5h reperfusion groups of HT have significant difference (P＜0.01),MCAO6h reperfusiongroups of NT have not significant difference (P＞0.05).
2.HT were lower significantly than NT in term of the infarction volume and score ofLonga and the water content of infarcted cerebra(MCAO2-5h reperfusion groups P＜0.01,MCAO6h reperfusion groups P＜0.05).
The mechanisms of prolonging treatment time window of restoration of bloodflow.(reperfusion)by mild hypothermia applied during reperfusion and cerebralprotection of it.
1.The study in the view of apoptosis
1.1HT and NT were higher significantly than sham-operation in term of AIF Cyt CandHSP70 (P＜0.01).
1.2HT were lower significantly than NT in term of AIF and Cyt C,HT were highersignificantly than NT in term of HSP70 (MCAO2-5h reperfusion groups P＜0.01,MCAO6h reperfusion groups P＜0.05).
1.3Compared with MCAO24h group in term ofAIF CytC and HSP70:MCAO2-4hreperfusion groups of NT have significant difference (P＜0.01),MCAO5-6h groupsreperfusion of NT have not significant difference (P＞0.05);MCAO2-5h reperfusiongroups of HT have significant difference (P＜0.01),MCAO6h reperfusiongroupsof NT have not significant difference (P＞0.05).
2.The study in the view of cerebral vasopermeability
2.1There was negative relationship between MMP-9and LN r=-0.817,P＜0.01).
2.2HT and NT were higher significantly than sham-operation in term of MMP-9 (P＜0.01).HT and NT were lower significantly than sham-operation in term of LN (P＜0.01)
2.3HT were lower significantly than NT in term of MMP-9,HT were highersignificantly than NT in term ofLN (MCAO2-5h reperfusion groups P＜0.01,MCAO6h reperfusion groups P＜0.05).
2.4Compared with MCAO24h group in term of MMP-9 and LN:MCAO2-4hreperfusion groups of NT have significant difference (P＜0.01),MCAO5-6h groupsreperfusion of NT have not significant difference (P＞0.05);MCAO2-5h reperfusiongroups of HT have significant difference (P＜0.01),MCAO6h reperfusiongroupsof NT have not significant difference (P＞0.05).
Conclusion:1.The study demonstrated that the mild hypothermia applied duringreperfusion can prolong the treatment time window of restoration of blood flow.(reperfusion therapy).The reason for that is its potential capability of cerebral protection,via inhibiting capas-e-dependent and caspase-independent pathways of apoptosis andpromoting the expr--ession of Hsp70 protein.In one word,mild hypothermia canthoroughly inhibit apoptosis;inhibiting the expression of MMP-9 protein so allevia--ting the injury of micro--circulation,promoting endurance of microcirculation suffe--red ischemia/reperfusion.
2.The study indicated that the mild hypothermia applied during reperfusion is thebest approach to extend the time window of restoration blood flow.(reperfusion).therapy,it can inhibit apoptosis in ischemic penumbra and alleviate the injury ofmicrocirculation and promote endurance of microcirculation suffered ischemia/reperfusion,thus in multiple way to interruput pathophysiology processing.It cansingnificently prolongthe time window.
In conclusion,mild hypothermia is superior to other treatment approach aimed atprolonging time window,whoses mechanism were single,pertinence were poor (notdirectly to pathophysiology),effection were less power;In particular,it accuratelyreplicated the acute ischemic stroke in human being.since it is impossible thatpatients with stroke would be able to be treated with mild hypothermia before onsetof symptoms of stroke.,so that the mild hypothermia applied during reperfusion stagehave better clinical practicability.,the way of hypothermia was maturate,it's easy tobe popularized;because the mild hypothermia applied during reperfusion haveall-around cerebral protection,,it must have the good perspective that combine itwith the means of restoration of blood flow such as thrombolysis and/or brainprotection agents as well.
引文
[1]SusinSA,LorenzoHK,ZamzamiN,etal.Molecular Characterization of mitochondrial apoptosis inducing factor[J].Nature,1999,97:441-446.
[2]Xu L,Yenari MA,Steinberg GK,et al.Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade[J].J Cereb Blood FlowMetab,2002,22(1):21-28.
[3]KimHK.Experimental Models of Cerebral Ischemia[J].Acta Anesthesisologica Scandinavica,1997,41 (111):91-92.
[4]Mayer TE,Haumann GF,Baranczyk J,et al.Dynamic CT Perfusion Imaging of Acute Stroke[J].AJNR,2000,21(8):1441-1449.
[5]KoizumiJ,YoshidaY,NakazawaT,etal.Experimental studies of ischemia brainedema.l.A new experimental Model of Cerebral Embolism in Rats in Which Recirculation Can Be Introduced in the Iscchemic;Area[J].Stroke,1986,8:1.
[6]Schrnid ELsaesser R,Zausinger S,Hungerhuber E,et al.A Critical Reevaluation of the Intraluminal Thread Model of Focal Cerebral Ischemia:Evidence of Inadvertent Premature Reperfusin and Subarachnoid Hemorrhage in Rats by Laser Doppler Flowmetry[J]Stroke,1998,29:2162-2170
[7]He J,Klag M J,Wu Z,et al.Stroke in the People's Republic of China:geograpliic variations in incidence and risk factors.Stroke,1995,26:2222-2227.
[8]刘鸣，卒中防治研究证据——预防进展更加令人鼓舞．[J]国外医学脑血管病分册，2001，9(3)：195 196．
[9]Larrey I.Memoirs of Military Service and Campaigns of the French Armies[M].Baltimore:Cushing,1814.35-37.
[10]Castillo J,Davalos A,Marrugat J,etal.Timing for fever related brain damage in acute ischemic stroke.Stroke,1998,29:2455-2460.
[11]Castillo J,Martinez F,Leira R,etal.Mortality and morbidity of acute cerebra linfarction related to temperature and basal analytic parameters.CerebrovascDis,1994,4:56-71.
[12]Fay T.Observations on generalized refrigeration in cases of severe cerebral trauma[J].Ass Res Nerv Ment Dis Proc,1945,24:611-619.
[13]Clifton GL,Jiang JY,Lyeth BG,et al.Marked protection by moderate hypothermia after experimental traumatic brain injury[J].J Cereb Blood Flood Flow Metab,1991,11(1):114-121
[14]Castillo J,Davalos A,Marrugat J,etal.Timing for fever related brain damage in acute ischemic stroke.Stroke,1998,29:2455-2460.
[15]Castillo J,Martinez F,Leira R,etal.Mortality and morbidity of acute cerebra linfarction related to temperature and basal analytic parameters.CerebrovascDis,1994,4:56-71.
[16]Kammersgaard LP,Jorgensen HS,Rungby JA,etal.Admission body temperature predicts long term mortality after acute stroke:the Copenhagen Stroke Study.Stroke,2002,33:1759-1762.
[17]Astrup J,Syom L.Branston NM et al.Cortical evoked potential and extracellular K+ and H+and critical levels of brain ischemia.Stroke,1977,8(1):51-57
[18]Sharp FR,Lu A,Tang Yet al.Mutiple molecular pcnumbras afterfocal cerebral ischemia.J Cereb Blood Flow Metab.2000;20:1011-1032.
[19]Dawson VL,Dawson TM,London ED,et a.l Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures[J].Proc N atlAcad SciUSA,1991,88(14):6368-6371
[20]A lessandri B,Bullock R.Glutamate and its receptors in the pathophysiology of brain and spinal cord injuries[J].Prog Brain Res,1998,116(14):303-330
[21][21]RoseME,Huerbin MB,Melick J,et a.l Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury[J].Brain Res,2002,943(1):15-22
[22]Loddick SA,RothwellNJ.Mechanisms of tumor necrosis factor alphaction on neurodegeneration:interactionwith insulin-like growth factor-1[J].ProcNatlAcad SciUSA,1999,96(17):9449-9451.
[23]The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.Tissue plasminogen activator for acute ischemic stroke[J].N Engl J Med,1995,333:1581-1587.
[24]A Scientific Statement From the Stroke Council of the American Stroke Association.Guidelines for the Early Management of Patients With Ischemic Stroke.Stroke,2003,34:1056-1084.
[25]Golanov EV,Christensen JD,Reis DJ.Role of potassium channels in the central neurogenic neuroprotection elicited by cerebellar stimulation in rat.Brain Res,1999,842:496-500
[26]Golanov EV,Reis DJ.Neuroprotective electrical stimulation ofcerebellar fastigial nucleus attenuates expression of periinfarction depolarizing waves (PIDS) and inhibits cortical spreading depression.Brain Res,1999,818:304--315
[27]Galea E,Golanov EV,Feinstein DL,et al.Cerebellar stimulation reduces inducible nitric oxide synthase expression and protects brain from ischemia.Am J Physiol,1998,274(6 Pt 2):H2035-H2045.
[28]邓志宽，董为伟，电刺激小脑顶核对局灶性脑缺血“治疗时间窗”影响的实验研究[J]中华医学杂志2003，83(1 3)．
[29]Okubo S,IgarashiH,Kanamatsu T,et al.FK-506 extende the therapeutic timewindow for thrombolysiswithout increaseing the risk of hemorrhagic transformation in an embolic rat strokemodel.Brain Res,2007,1143(4):221-227.
[30]Zhang ZG,ChoppM,GoussevA,et al.Cerebralmicrovas-cular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onsetof focal embolic ischemia in rats.J Neurosc,i 1999,19(24):1089-1095.
[31]Straub S,JunghansU,JovanovicV,etal.Systemic thromboly-siswith recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion.Stroke,2004,35(3):705-709.
[32]Seitz R J,Meisel S,MollM,et al.The effect of combined thrombolysiswith rtPA and tirofiban on ischemic brain lesions.Neurology,2004,62(11):2110-2112.
[33]赵瑞波，张玉华，李宗敏，王德生，亚低温延长脑梗死治疗时间窗及其机制[J] 中华神经科杂志，2005，38(6)
[34]曹霞，曹秉振，郭述苏，大鼠大脑中动脉局灶性脑缺血模型的时间梗死体积相关研究[J]解放军医学杂志2000，25(2)
[35]Zhang RL,Chopp M,Chen H,et a.l Postischemic (lhour) hypothermia significantly reduces ischemic celldamage in rats subjected to 2 hours ofmiddle cerebral artery occlusion.Stroke,1993,24:1235-1240.
[36]Zhang ZG,ChoppM,Chen H.Duration dependent post-ischemic hypothermia alleviates cortical damage after transientmiddle cerebral artery occlusion in the rat.JNeurolSc,i 1993,117:240-244.
[37]Frederick C,Dale C,ZongHZ,et a.l Prolonged but delayed postischemic hypothermia:a long-term outcome study in the rat middle cerebral artery occlusion mode.1 J CerebBlood FlowMetab,2000,20:1702-1708.
[38]Corbett D,Hamilton M,Colbourne F,et a.l Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transientmiddle cerebral artery occlusion.Exp Neuro,l 2000,163:200-206.
[39]KollmarR,SchabitzWR,Heiland S,et a.l Neuroprotective effectofdelayedmoderate hypothermia after focal cerebral ischemia:an MRI study.Stroke,2002,33:1899-1904
[40]Dawson,Jesse,etal.New and emerging treatments for stroke British Medical Bulletin (C) British Council 2006.Oxford University Press.Volume 77-78(1),2006,pp 87-102
[41]ErecinskaM,ThoresenM,Silver IA,etal.Effects ofhypothermia on energymetabolism inMammalian centralnervous system,2003,23 (5):513-530.
[42]HaradaK,Maekawa T,Tsuruta R,et al.Hypothermia inhibits translocation ofCaM kinase II and PKC-alpha,beta,gamma isoforms and fodrin proteolysis in rat brain synaptosome during ischemia-reperfusion.JNeurosciRes,2002,67 (5):664-669.
[43]PrandiniMN,Neves Filho A,Lapa AJ,et al.Mild hypothermia reduces polymorphonuclear leukocytes infiltration in induced brain inflammation,2005,63 (3B):779-784.
[44] VanHemelrijckA, Vermijlen D, Hachimi-Idrissi S, et al • Effect of resuscitative mild hypothermia on glutamate and dopamine release, apoptosis and schaemic brain damage in the endothelin-1rat model for focal cerebral ischaemia • J Neurochem • 2003, 87(1): 66-75 •
[45] BergerC, SchabitzWR, GeorgiadisD, et al • Effects of hypothermia on excitatory amino acids andmetabolism in stroke patients: amicrodialysis study • Stroke, 2002, 33 (2): 519-524 •
[46] HoriguchiT, ShimizuK, OginoM, etal • Postischemic hypothermia inhibits the generation of hydroxy1 radical following transient forebrain ischemia in rats • JNeurotrauma, 2003, 20 (5): 511-520 •
[47] MaierCM, Sun GH, ChengD, et al • Effects ofmild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia • Neurobio Dis, 2002,11 (1): 28-42 •
[48] VanHemelrijckA, Hachimi-Idrissi S, Sarre S, et al • Post-ischaemic mild hypothermia inhibits apoptosis in the penumbral region by reducing neuronalnitric oxide synthase activity and thereby preventing endothelin 1-induced hydroxy1 radical formation • Eur JNeurosc,i 2005, 22 (6): 1327-1337 •
[49] Yanamoto H,Nagata I,Niitsu Y,et al.Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia.Stroke, 2001,32(l):282 289.
[50] Huh PW, Belayev L,Zhao W, et al.Comnrative neuroprotective efficacy of peolonged moderate intraischemic and postischemic hypothermia in focalcerebral ischemicaJ Nerosurg, 2000,92(l):91 99.
[51] Ferrer I, Planas Am. Signaling of cell death and cell survival following focalcerebral ischemia: life and death struggle in the penumbra. J Neuropathol ExpNeurol,2003,62(4):329-339.
[52] Kerr J F, Wyllie A H, Currie A R. Apoptosis: a basis biologica phenomenonithide-ranging implications in tissue kinetics. Br JCancer, 1972, 26: 239—257
[53] Vermeulen K, Van Bockstaele DR, Berneman ZN. Apoptosis:mechanisms and relevance in cancer. Ann Hemato,l 2005, 84(10): 627—639
[54]VauxDL.Apoptosis timeline.CellDeathDiffer,2002,9:349-354
[55]Johnson KL,VaillantF,LawenA.Protein tyrosine kinase inhibitors prevent didenmin B-induced apoptosis in HL-60 cells.FEBSLett,1996,383:1-5
[56]EdingerAL,Thompson CB.Death by design:apoptosis,necrosis and autophagy.CurrOpin CellBio,1 2004,16(6):663-669
[57]SarisNE,Carafoli E.A historical review of cellular calcium handling with emphasis on mitochondria[J].Biochemistry (Moscow),2005,70 (2):187-194.
[58]Lim M L,Lum M G,Hansen T M,et al.On the release of cytochrome c from mitochondria during cell death signaling[J].JBiomed Sci,2002,9:488-506.
[59]Loo G,Saelens X,Gurp M,et al.The role ofmitochondrial factors in apoptosis:a russian roulette with more than one bullet[J].Cell Death Differ,2002,9(10):1031-1042.
[60]Ferrer I,Friguls B,Dalfo E,et al.Caspase-dependent and caspase-independent signaling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat[J].Neuropathology &Applied Neurobiology,2003,29:472(479.
[61]Himda T,Tounai H,HayakaWa N,etal.Postichemical tertions of DNF,NGF,HSP 70 and Ubiquitin Immunoreactivity in the Gerbil Hippocampus:Pharmacoogical Approach[J].CellMolNeurobiol,2007,27(2):229-250.
[62]SamaliA,CotterTG.Heat shoek proteins inerease resistance to apoptosis[J 1.ExPerimentalCellReseareh,1996,223 (1):163-170.
[63]Susin SA et al.Molecular characterization of mitochondrial apoptosis inducing factor.Nature,1999;397(6718):441
[64]Otera H et al.Export ofmitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space.EMBO J,2005,24(7) 1375 1386
[65]Susin SAet al.Two distinct pathways leading to nuclear apoptosis.J Exp Med,2000;192(4):571
[66]Zhang Xet al.Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite.J Neurochem,2002;82(1):181
[67]Yu SWet al.Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.Science,2002;297(5579):259
[68]Li Y,Chopp M,Jiang N,et al.Induction of DNA fragmentation after 10 to 120 minutes of focal cerebral ischemia in rats.Stroke,1995,26(7):1251-125 3.
[69]Ye Het al.DNA binding is required for the apoptogenic action of apoptosis inducing factor.Nat Struct Biol,2002;9(9):680
[70]Lipton SAet al.Dueling activities of AIF in cell death versus survival:DNA binding and redox activity.Cell,2002;111(2):147
[71]Zou H,Li Y,Liu Xet al.An Apaf-l.cytochrome C multimeric complex is a functional apoptosome that activates procaspase-9.JBiol Chem,1999;274(17):11549-56.
[72]Hu Y,Benedict MA,Ding Let al.Role of cytochrome C and dATP/ATP hydrolysis in Apaf-l-mediated caspase-9 activation and apoptosis.EMBO J,1999;18(13):3586-95.
[73]Saleh A,Srinivasula SM,Acharya Set al.Cytochrome C and dATP-rnediated oligomerization of Apaf-1 is a prerequisite for pro-caspase-9 activation.JBiol Chem,1999;274(25):17941-5.
[74]Enari M,Sakahira H,Yokoyama Het al.A caspase-activated DNase that degrades DNA during apoptosis,and its inhibitor I-CAD.Nature,1998;391(6662):43-50
[75]Pocai Aet al.A brain-liver circuit regulates glucose homeostasis.Cell Metab,2005,1 (1):53 61
[76]Kroemer G,Zamzami N,Susin SA.Mitochondrial control of apoptosis.ImmunolToday,1997;18(1):44-51
[77]Maurer M,Tsai M,Metz Met al.A role for Bax in the regulation ofapoptosis in mouse mast cells.J Invest Dermatol,2000;114(6):1205-6
[78]Kudla G,Montessuit S,Eskes Ret al.The destabilization of lipid membranes induced by theC-terminal fragment of caspase 8-cleaved bid is inhibited by theN-terminal fragment.JBiol Chem,2000;275(30):22713-8
[79]Yenari MA,Iwayama S,Cheng D,et al.Mild hypothermia attenuates cytochrome c release but does not alter Bcl-2 expression or caspase activation after experimental stroke[J].J Cereb Blood Flow Metab,2002,22(1):29-38.
[80]FerriKF,JacototE,Blanco J,eta.l Apoptosis control syncytia induced by the HIV-1-envelope glycoprote complex.Role ofmitochondria and caspases[J].J Ex Med,2000,261(1):119-126.
[81]谷文萍，谢光洁，杨期东．热休克蛋白70研究进展[J]．国外医学神经病学神经外科学分册，1999，26(2)：57-59．
[82]Polla B S,Kantengwa S,Francois D,et al.Mitochondria are sclective targets for the protective effects of heat shock against oxidative injure[J].Proc Natl Acad Sci USA,1996.93(13):6458-6463
[83]Pandey P,Saleh A,Nakazawa Aet al.Negative regulation of cy-tochrome C-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90.EMBO J,2000;19(16):4310-22
[84]RenM,LengY,JeongM,eta.l Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats potential roles ofhistone deacetylase inhibition and heatshock protein induction[J].JNeurochem,2004,89(6):1358-1367.
[85]KokuboY,Liu J,Rajdev S,eta.1 Differential cerebralprotein synthesis and hea shock protein 70 expression in the core and penumbra ofratbrain after transient focal ischemia[J].Neurosurgery,2003,53(1):186-190.
[86]Juliann G K,George C T.Heat shock protein 70 kDa:molecular biology,biochemistry and physiology[J].Pharmacol Ther,1998,80(2):184-185.
[87]Wang X,Lee SR,etal.Lipoprotein receptor mediated induction of matrix metalloproteinase by tissue plasminogen activator.Nat Med,2003,9:1313-1317.
[88]Libby P.Changing concepts ofatherogenesis[J].J Intem Med,2000,247:349-358.
[89]Kleiner DE,Stevenson WG.Matrix metelloproteinases and metastasis[J].Cancer Chemother Pharmacol,1999,43[Suppl]:S42-S51
[90]Birkedal-Hansen H,Moore WG,Bodden MK,et al.Matrix metalloproteinases:a review[J].Crit Rev Oral Biol Med,1993,4:197-250.
[91]Leco KJ,Khokha R,PavloffN,et al.Tissue inhibitor of metalloproteinases-3-(TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues[J].J BiolChem,1994,269:352-9360.
[92] Zhang WW,Badionic T,Hoog A.Structural and vasoactive factor influencing intracerebral in case of vasular demendia and other cerebral in case of vascular dementia and other cerebrovascular:a renew.Dementia, 1994,5:153 -162.
[93] Heo JH,KimSH,etal.Increase in plasma matrix metalloproteinase 9in acute stroke patients with thrombolysis failure.Stroke,2003,34: e 48- e 50.
[94] Wojtowicz-Praga SM, Dickson RB,Hawkins MJ.Matrix metelloproteinease Inhibitors[J].Invest New Drugs 1997,15(l):61-75.
[95] Tabot DC,Brown PD.Experimental and clinical studies on the use of Matrix metelloproteinases inhibitors for the treatment of cancer[J].EurJCancer,1996, 32A(14):2528-2533
[96] Apte SS,Mattei MG,Olsen BR.Cloning of the cDNA encoding humantisue inhibitor of metallopmteinases-3(TIMP-3) and mapping of the TIMI-gene tochromosome 22 [J] .Genomics, 1994,19(1): 86-90.
[97] BrewK,Dinakarpandian D,NagaseH.Tissue inhibitors ofmetalloprotein sesevolution, structure and function [J]. Biochim Biophys Acta,2000, 477(l-2):267-283.
[98] Pfefferkorn T,Rosenberg GA.Closure of the blood-brain barrier by matrix metalloproteinase inhibition ReducesrtPA-mediatedmortality in cerebral ische--mia with delayed reperfusion[J].Stroke,2003,34(8): 2025-2030.
[99] Krekoski CA,Neubauer D,Graham JB,et al.Metalloproteinase-dependent predegeneration in vitro enhances axonal regenerationwithin Acellular peripheral nerve grafts[J].J Neurosci,2002,22(23):10408-10415.
[100] Deng H, Han HS, Cheng D,et al. Mild hypothermia inhabits inflammation after experimental stroke and brain inflammation[J].Stroke, 2003, 34(10): 2495-2501.
[101] HaradaK, Maekawa T, Tsuruta R, et al • Hypothermia inhibits translocation ofCaM kinase II and PKC-alpha, beta, gamma isoforms and fodrin proteolysis in rat brain synaptosome during ischemia - reperfusion • JNeurosciRes, 2002, 67 (5):664-669.
[102]Yang GY,et al.Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats.Stroke,1994;25:1658
[1] Popovic, R., Liniger, R., et al. (2000). Anesthetics and mild hypothermia similarly prevent hippocampal neuron death in an in vitro model of cerebral ischemia. Anesthesiology 92, 1343-1349.
[2] Larrey I. Memoirs of Military Service and Campaigns of the French Armies [M]. Baltimore:Cushing,1814.35-37.
[3] Fay T. Observations on generalized refrigeration in cases of severe cerebral trauma [ J ]. Ass Res Nerv Ment Dis Proc,1945,24:611-619.
[4] Hammer, Krieger, et al. Hypothermia for Acute Ischemic Stroke: Not Just Another Neuroprotectant [J]. The Neurologist (C) 2003 Lippincott Williams & Wilkins, Inc. Volume 9(6), November 2003,280-289
[5] Clifton GL, Jiang JY, Lyeth BG, et al. Marked protection by moderate hypothermia after experimental traumatic brain injury[J]. J Cereb Blood Flood Flow Metab,1991,11(1):114-121
[6] Clifton GL,Miller ER,Choi SC,et al.Lack of effect of induction of hypothermia after acute brain injure [J]N Engl J Med,2001,344(8):556-563.
[7] Castillo J, Davalos A, Marrugat J, etal. Timing for fever related brain damage in acute ischemic stroke. Stroke, 1998, 29:2455-2460.
[8] Castillo J, Martinez F, Leira R, etal. Mortality and morbidity of acute cerebra linfarction related to temperature and basal analytic parameters.CerebrovascDis, 1994,4:56-71.
[9] Fisher, M., for the Stroke Therapy Academic Industry Roundtable.(2003). Recommendations for advancing development of acute stroke therapies: Stroke Therapy Academic Industry Roundtable 3. Stroke 34, 1539-1546..
[10] Nolan, J.P., Morley, P.T., et al. (2003). Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation 108, 118-121..C
[11] Adams, H., Adams, R., et al. (2005). Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association.Stroke 36, 916-923..。
[12] Krieger, D.W., De Georgia, M.A., et al. (2001). Cooling for acute ischemic brain damage (COOL AID): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 32,1847-1854.
[13] Mayer, S.A., Kowalski, R.G., et al. (2004). Clinical trial of a novel surface cooling system for fever control in neurocritical care patients. Crit. Care Med. 32,2508-2515
[14] Zweifler, R.M., Mahmood, V.M., et al. (2003). Induction and maintenance of mild hypothermia by surface cooling in nonintubated subjects. J. Stroke Cerebrovasc. Dis. 12,237-243.
[15] Baumgardner, J.E., Baranov, D., et al. (1999). The effectiveness of rapidly infused intravenous fluids for inducing moderate hypothermia in neurosurgical patients. Anesth. Analg. 89,163-169.
[16] Mack, W.J., Huang, J., et al. (2003). Ultrarapid, convectionenhanced intravascular hypothermia: a feasibility study in nonhuman primate stroke. Stroke 34, 1994-1999.
[17] Maier, CM., Sun, G.H., Kunis, D., Yenari, M.A., and Steinberg,G.K. (2001). Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia:neurological outcome and infarct size. J. Neurosurg. 94,90-96
[18] Barone, F.C., Feuerstein, G.Z., and White, R.F. (1997). Brain cooling during transient focal ischemia provides complete neuroprotection. Neurosci. Biobehav. Rev. 21,31-44
[19] Huh, P.W., Belayev, L., Zhao, W., Koch, S., Busto, R., and Ginsberg, M.D. (2000). Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia. J. Neurosurg. 92, 91-99
[20] Kollmar, R., Blank, T., Han, J.L., Georgiadis, D., and Schwab, S.(2007). Different degrees of hypothermia after experimental stroke: short- and long-term outcome. Stroke 38, 1585-1589
[21] Schwab, S. (2005). Therapy of severe ischemic stroke: breaking the conventional thinking. Cerebrovasc. Dis. 20, Suppl 2,169-178.
[22] Mokhtarani, M., Mahgoub, A.N., Morioka, N., Doufas, A.G.,Dae, M., Shaughnessy, T.E., Bjorksten, A.R., and Sessler, D.I.(2001). Buspirone and meperidine synergistically reduce theshivering threshold. Anesth. Analg. 93, 1233-1239.
[23] Guluma, K.Z., Hemmen, T.M., Olsen, S.E., Rapp, K.S., and Lyden, P.D. (2006). A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad. Emerg. Med. 13,20-827.
[24] Schwab, S., Schwarz, S., Spranger, M., Keller, E., Bertram, M.,and Hacke, W. (1998). Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 29, 2461-2466
[25] Steiner, T., Friede, T., Aschoff, A., Schellinger, P.D., Schwab, S.,and Hacke, W. (2001). Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery. Stroke 32, 2833-2835
[26] De Georgia, M.A., Krieger, D.W., Abou-Chebl, A., Devlin, T.G.Jauss, M., Davis, S.M., Koroshetz, W.J., Rordorf, G., and Warach, S. (2004). Cooling for Acute Ischemic Brain Damage(COOL AID): a feasibility trial of endovascular cooling. Neurology 63, 312-317
[27] Lyden, P.D., Allgren, R.L., Ng, K., Akins, P., Meyer, B., Al-Sanani, F., Lutsep, H., Dobak, J., Matsubara, B.S., and Zivin, J.(2005). Intravascular Cooling in the Treatment of Stroke (ICTuS):early clinical experience. J. Stroke Cerebrovasc. Dis. 14,107-114
[28] MaierMaier, CM., Sun, G.H., Kunis, D., Yenari, M.A., and Steinberg, G.K. (2001). Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia:neurological outcome and infarct size. J. Neurosurg. 94,90-96
[29] KollmarKollmar, R., Frietsch, T., Georgiadis, D., Scha" bitz, W.R.,Waschke, K.F., Kuschinsky, W., and Schwab, S. (2002). Early effects of acid-base management during hypothermia on cerebral infarct volume, edema, and cerebral blood flow in acute focal cerebral ischemia in rats. Anesthesiology 97, 868-874.
[30] Yanamoto, H., Nagata, I., Nakahara, I., Tohnai, N., Zhang, Z.and Kikuchi, H. (1999). Combination of intraischemic and postischemic hypothermia provides potent and persistent neuroprotection against temporary focal ischemia in rats.Stroke 30, 2720-2726
[31] Yanamoto, H., Hong, S.C., Soleau, S., Kassell, N.F., and Lee, K.S.(1996). Mild postischemic hypothermia limits cerebral injury following transient focalischemia in rat neocortex. Brain Res.718,207-211.)
[32] Yanamoto, H., Nagata, I., et al. (1999). Combination of intraischemic and postischemic hypothermia provides potent and persistent neuroprotection against temporary focal ischemia in rats. Stroke 30,2720-2726
[33] Dietrich, W.D., Busto, R., et al. (1993). Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J. Cereb Blood Flow Metab. 13, 541-549
[34] Colbourne, F., Li, H., et al. (1999). Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats. J. Cereb. Blood Flow Metab. 19, 742-749
[35] Ohta H, Terao Y,etal, Therapeutic time window of post-ischemic mild hypothermia and the gene expression associated with the neuroprotection in rat focal cerebral ischemiaJ Neurosci Res. 2007 Mar;57(3):424-33. Epub 2007 Jan 8.
[36] Dawson, Jesse ,etal. New and emerging treatments for stroke British Medical Bulletin (C) British Council 2006. Oxford University Press. Volume 77-78(1), 2006, pp 87-102
[37] Zhang RL, Chopp M, ChenH, etal. Postischemic(1hour) hypothermia significantly reduces ischemic cell dam age in rats subjected to 2hours of middle cerebral artery occlusion.Stroke,1993,24:1235 1240.
[38] Zhang ZG, Chopp M, ChenH. Duration dependent post ischemic hypothermia alleviates cortical damage after tran sient middle cerebral artery occlusion in the rat.JNeurolSci, 1993,117:240 244.
[39] Frederick C, Dale C, ZongHZ, etal. Prolonged but de layed postischemic hypothermia: a long term outcome study in the rat middle cerebral artery occlusion model.J Cereb Blood Flow Metab,2000,20:1702 1708.
[40] Corbe tt D, Hamilton M,Colbourne F, etal. Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion. ExpNeurol, 2000, 163:200 206.
[41] Kollmar R, Schabitz WR, Heiland S, etal. Neuroprotective effect of delayed moderate hypothermia after focal cere bral ischemia: an MRI study. Stroke,2002,33:1899 1904.
[42] Colbourne, F., Corbett, D., et al. (2000). Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J. Cereb. Blood Flow Metab. 20,1702-1708
[43] Maier, CM., Sun, G.H., et al. (2001). Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J. Neurosurg. 94, 90-96
[44] Barone, F.C., Feuerstein, G.Z., and White, R.F. (1997). Brain cooling during transient focal ischemia provides complete neuroprotection. Neurosci. Biobehav. Rev. 21,31-44
[45] Colbourne, F., and Corbett, D. (1995). Delayed postischemic hypothermia: a six-month survival study using behavioral and histological assessments of neuroprotection. J. Neurosci. 15, 7250-7260
[46] Roelfsema, V., Bennet, L., et al. (2004). Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep. J. Cereb. Blood Flow Metab. 24, 877-886
[47] Hacke, W., Donnan, G., Fieschi, C., Kaste, M., von Kummer, R.,Broderick, J.P., Brott, T., Frankel, M., Grotta, J.C., Haley, E.C.,Jr., Kwiatkowski, T., Levine, S.R., Lewandowski, C., Lu, M.,Lyden, P., Marler, J.R., Patel, S., Tilley, B.C., Albers, G.,Bluhmki, E., Wilhelm, M., and Hamilton, S. (2004). Associationof outcome with early stroke treatment: pooled analysis ofATLANTIS, ECASS, andNINDS rt-PA stroke trials. Lancet363, 768-774.
[48] Wolberg, A.S., Meng, Z.H., et al. (2004). A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J. Trauma 56, 1221-1228.
[49] Sumii, T., and Lo, E.H. (2002). Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33, 831-836
[50] Lyden, P.D., Krieger, D., et al. (2006). Therapeutic hypothermia for acute stroke. Int. J. Stroke 1,9-19
[51] Rogalewski, A., Schneider, A., et al. (2006). Toward a multimodal neuroprotective treatment of stroke. Stroke 37, 1129-1136.
[52] Cheng, Y.D., Al-Khoury, L., et al. (2004). Neuroprotection for ischemci stroke: two decades of success and failure. NeuroRx 1, 36-45.
[53] Zausinger, S., Scholler, K., et al. (2003). Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Stroke 34, 2246-2251
[54] Kader A,MassaroAR,Young WL,et al.Characterization of arteriovenous malformation feeding vessls by carbon dioxide reactivity.Neuroradiol, 1994,15(1):55.
[55] Dempsey RJ,Slevin JT,Slevin JT,Sparks DL,rt al.Altered striatal dopaminergic metabolism 36hours after unilateral trauma to the human mesencephalon.Neurology, 1987,37(2):322.
[56] Akira T, Ishihara S,Anada T,et al.Surface cooling reduces survival time after lethal volume controlled hemorrhage in pigs.Acad Emerg Med, 1999,6(5):477.
[57] Yanamoto H,Nagata I,Niitsu Y,et al.Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia.Stroke, 2001,32(l):282 289.
[58] Huh PW, Belayev L,Zhao W, et al.Comnrative neuroprotective efficacy of peolonged moderate intraischemic and postischemic hypothermia in focalcerebral ischemica.J Nerosurg, 2000,92(l):91 99.
[59] Schwab S,Schwarz S,A schoff A,et al.Moderate hypothermia and brain temperature in patients with severe middle cerebral artery infarction.Acta Neurochir Suppl, 1998,71:131 134.
[60] Wieloch T,Borls MO.High time to test hypothermia in the treatment of stroke.Lakartidningen, 2001,98(18):2172-2175.
[61] Tomasevic G,Shamloo M,Israeli D,et al.Activation of p53 and genes p21 and PAG608/Wig1 inischemic preconditioning.Brain Res Mol Brain Res,1999,70(2):304 313.
[62] Colbourne F,Auer RN,Sutherland GR.Behavioral testing dose not exerciate ischemic XAldamage in gerbils.Stroke,1998,29(9):1967-1970.
[63] Bossenmeyer Pourie C,Koziel V,Daval JL.Effects of hypothermia on innpoxia-induce apoptosis in cultured neuron from developing rat forebrahr.common with preconditioning.Pediatr Res, 2000,47(3):385-391.
[64] Bokesch PM,March and J,Seirafi PA,et al.Immediate early gene expression in ovine brain after cardiopulmonary bypass and hypothermic circulatory arrest,Anesthesiology, 1996,85(6): 1439-446.
[65] KumarK,WuX,Evans AT,et al.The effect of hypothermia on induction of heat shock protein(HSP) 72 in ischemic brain.Metab Brain Dis,1995,10(4):281-291.
[66] KerrJF,WyllieAH,CurrieAR.Apoptosis:a basis biological phenomenon with wide-ranging implications in tissue kinetics. BrJCancer, 1972, 26:239-257.
[67] Mate M Jetal. The crystal structure of the mouse apoptosis-inducing factor AIF.Nat Struct Biol, 2002;9(6):442
[68] Ye H et al. DNA binding is required for the apoptogenic action of apoptosis inducing factor.Nat Struct Biol, 2002;9(9):680
[69] Ferrer I,Planas AM.Signaling of cell death and cell survival following focal cerebral ischemia:life and death struggle in the penumbra.J Neu ropathol Exp Neurol,2003,62:329-339.
[70] Cain K,Bratton SB,Langlais C,et al.Apafl oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4MDa apoptosome complexes J Biol Chem,2000,275:6067-6070.
[71] Susin SA,Lorenzo HK,Zamzami N,etal.Molecular characterization of mitochondrial apoptosis inducing factor IF[J].Nature,1999,397(6718):441
[72] Yenari MA, Iwayama S, Maier CM,et al: Influence of mild hypothermia On Bc1-2/Bax expression and cytochrome c release following experimental stroke. AM. Academy of Neurology.2000; 34: 26-31.
[73] Xu L,Yenari MA, Steinberg GK, et al; Mild Hypothermia Reduces Apoptosis of Mouse Neurons In Vitro Early in the Cascade. J Cereb Blood Flow Metab.2002;22(l):21-28.
[74] Yenari MA, Iwayama S, Steinberg GK,et al; Mild Hypothermia Attenuates Cytochrome C Release but Does Not Alter Bc1-2 Expression or Caspase Activation After Experimental Stroke. J Cereb Blood Flow Metab.2002;22(l):29-38.
[75] Wang LS, Yu LJ, etal. Mild hypothermia attenuates neuronal apoptosis after cerebral hypoxia-ischemia in neonatal rats .J Zhongguo Dang Dai Er Ke Za Zhi. 2007 Feb;9(l):37-41.
[76] Adachi M, Sohma O,Tsuneishi S, etal Combination effect of systemic hypothermia and caspase inhibitor administration against hypoxic ischemic brain damage in neonatal rats[J]. PediatrRes, 2001, 50(5):590-5.
[77] XuL,Yenari MA,Steinberg GK,Giffard RG.Mildhypothermia reduces apoptosis of mouse neurons in vitro early in the cascade[J].JCerebBloodFlow Metab,2002,22(l):21-28.
[78] Zhao H, Wang JQ, etal. Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion. [J]Neurosurg. 2007 Sep;107(3):636-641
[79] Plesnila N,Zhu C,Culmsee C,etal.Nuclear translocation of apoptosis inducing factor after focal cerebral ischemia [J].JCerebral Blood Flow Metab,2004,24(4):458 466.
[80] Culmsee C, Zhu C,Landschamer S,etal.Apoptosis inducing factor triggered by poly(ADP ribose)polymerase and Bid mediates neuronal cell death after oxygen glucose deprivation and focal cerebral ischemia [ J ].J Neurosci, 2005,25(44): 10262 10272.
[81]Cheng ZG,Yu P,Wang YJ,Li JY,Huang JF,Guo QL,Tan XJ.Effects of selective head mild hypothermia on endogenous neuroprotection in brain following global cerebral ischemia/reperfusion injury:experiment with dogs.[J]J.Zhonghua Yi Xue Za Zhi.2007 May 22;87(19):1318-21.
[82]陈兴洲，陆兵勋．基质金属蛋白酶与脑血管病[J]．国外医学：脑血管病分册，1999，7：197-200．
[83]LibbyP.Changingconceptsofatherogenesis[J].JIntemMed,2000,247:349-358.
[84]Sumii T,Lo EH.Involvement of matrix metalloproteinase in thrombolysis associated hemorrhagic transformation after embolic focal ischemia in rats.Stroke,2002,33:831-836.
[85]Montaner J,Alvarez Sabin J,Molina CA,et al.Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke.Stroke,2001,32:2762-2767.
[86]Castellanos M,Leira R,Serena J,et al.Plasma metalloproteinase 9concentration predicts hemorrhagic transformation in acute ischemic stroke.Stroke,2003,34:40-46.
[87]Wang X,Lee SR,etal.Lipoprotein receptor mediated induction of matrix metalloproteinase.by tissue plasminogen activator.Nat Med,2003,9:1313-1317.
[88]Montaner J,Fernandez Cadenas I,etal.Safety profile of tissue plasminogen activator treatment among stroke patients carrying acommon polymorphism (C 1562 T)in the promoter region of the matrix metalloproteinase 9gene.Stroke,,2003,34:2851-2855.
[89]Pfefferkom T,Rosenberg GA.Closure of the blood brain barrier by matrix metalloproteinase inhibition reduce rt-PA mediated mortality in cerebral ischema with delayed reperfusion.Stroke,2003,34:2025-2030
[90]Fasciglione GF,Marini S,D'Alessio S,Politi V,Coletta M.pH-and temp era ture-dependence of functional modulation in metalloproteinases.A comparison between neutrophil collagenase and gelatinases A and B.Biophys J.2000;79:2138-2149.
[91]Hamann GF,BurggrafD,Martens HK,Liebetrau M,J(a|¨)ger G,Wunderlich N, Mild to moderate hypothermia prevents microvascular basal lamina antigen loss in experimental focal cerebral ischemia.[J]JStroke. 2004 Mar;35(3):764-9.Epub 2004 Feb l9
[92] Solveig Horstmann, MD et al. Profiles of Matrix Metallo proteinases, Their Inhibitors,and Laminin in Stroke Patients Influence of Different Therapies . Stroke 2003 ;34;2165-2170