依达拉奉对于急性脑梗死溶栓患者MMP－9水平及出血性转化的影响

依达拉奉对于急性脑梗死溶栓患者MMP-9水平及出血性转化的影响

陈春燕孙晓江陆学胜

(上海交通大学附属第六人民医院神经内科，上海200233)

关键词〔〕依达拉奉;重组组织型纤溶酶原激活物;基质金属蛋白酶-9;出血性转化

中图分类号〔〕R743.3〔文献标识码〕A〔

通讯作者：孙晓江(1955-)，男，教授，主任医师，博士生导师，主要从事脑血管病、癫痫等研究。

陆学胜(1965-)，男，主任医师，主要从事脑血管病、癫痫等研究。

第一作者：陈春燕(1982-)，女，在读硕士，主要从事脑血管病研究。

重组组织型纤溶酶原激活物(rt-PA)是美国食品和药品监督管理局(FDA)唯一批准使用于急性缺血性卒中溶栓治疗的药物，时间窗内rt-PA静脉溶栓为目前公认的改善缺血性卒中结局最有效的治疗方法，有效改善血管再通及神经功能损伤〔1〕。NINDS〔2〕、亚特兰蒂斯(ALTLANTIS)以及欧洲协作急性卒中研究(ECASS)等临床研究结果都证明了卒中3 h内使用rt-PA静脉溶栓安全有效〔3〕，ECASSⅢ用13年研究把时间窗扩大到4.5 h〔4〕，然而短暂的时间窗的限制和出血性转化(HT)的风险成了限制溶栓治疗最主要的因素，rt-PA溶栓治疗出HT概率为非溶栓的10倍〔2，5〕。如何降低出血风险，提高溶栓的疗效成为关注的重点，近年的研究发现了基质金属蛋白酶(MMP)-9在出HT中的关键作用，而依达拉奉能安全有效地抑制和降低MMP-9水平。

1血脑屏障(BBB)

急性脑梗死rt-PA溶栓后HT，实质为BBB的破坏。BBB结构完整可以保护神经元的微环境，主要有三方面组成：脑的连续毛细血管内皮及其细胞间的紧密连接〔6〕、完整的基膜〔7〕、周细胞以及星形胶质细胞脚板围成的神经胶质膜构成，其中内皮是BBB的主要结构。急性脑梗死2 h后这些血管内皮基底膜结构开始出现损伤〔8〕，当内皮和紧密连接蛋白受到破坏及基底膜遭降解损伤后，BBB的完整性破坏，炎症因子和液体等渗入脑组织，引起细胞死亡，脑水肿和出血性转化。这种情况在老年人反应和损伤比中年人更为严重〔9〕。研究发现MMP-9在脑代谢的病理生理过程中尤其是HT、BBB的破坏起了很关键的作用〔10〕。MMP-9可以水解细胞内皮细胞内紧密连接蛋白结构而损伤BBB〔11〕，MMP-9缺乏的小鼠表现较少的BBB裂开和脑损伤〔12〕。

正常脑组织中MMP-9无表达或少量表达〔13〕，缺血再灌注后MMP-9水平迅速升高〔14〕，溶栓后 MMP-9表达上调的原因可能与下列因素有关：(1)缺血再灌注诱发炎症反应，产生大量炎性因子和介质诱导MMP-9生成〔15〕，(2)氧化应激产生大量自由基〔16〕，促进MMP-9表达〔17〕并损伤微血管导致血管破裂，用自由基清除剂可减少t-PA引起的出血，(3)rt-PA能激活MEK，并进一步使ERK磷酸化而活化，从而促进MMP-9基因的表达〔18〕，(4)rt-PA为纤溶酶原激活剂，其纤维蛋白在MMP-9的激活过程中起了重要作用，从而使MMP-9表达增加，对脑血管的基底膜降解作用进一步增强而引起HT〔19〕。

体外研究发现rt-PA可诱导血管内皮细胞MMP-9的表达〔20〕，临床试验发现rt-PA溶栓后MMP-9大量表达〔21〕，McColl等〔13〕报道rt-PA溶栓后MMP-9活性进一步增加，而对照组未见有MMP-9活性的改变。第一项研究显示在人类大脑卒中后MMP-9的升高是由Clark等〔22〕完成的，表明脑梗后2 d的人类大脑组织MMP-9活动较没有脑梗的明显提高。随后临床研究资料证实MMP-9在卒中的关键因素和再灌注期间其有害影响〔21〕，MMPs家族中仅仅MMP-9表达显著增加与HT换的主题相关〔23〕。一项扩大实验327名溶栓患者(年龄68.9±12.1，NIHSS平均11分)，检测所有MMPS家族(1,2,3,7,8,9)发现仅MMP-9有明显变化，与HT和死亡率相关〔24〕，Mallolas等〔25〕发现基线水平的MMP-9升高是静脉内使用rt-PA治疗造成脑出血的独立预测因素，MMP-9可以作为生化标志物预测溶栓后HT〔26〕。最近的数据证实高MMP-9水平不仅在梗死组织还在临近组织区域,这表明MMP-9参与梗死区域扩大的过程〔27〕，高水平的MMP-9明显和脑梗死体积大、程度严重及预后差相关〔28〕，在急性脑梗死死亡患者中MMP-9 mRNA的浓度为存活者的3倍〔29〕，因此MMP-9 mRNA是卒中患者预后差、死亡率高的预测值。第一个研究MMP-9敲除小鼠(KO)模型以来均显示MMP-9 KO小鼠运动缺陷低于野生型(WT)小鼠〔30〕，在MMP-9局灶脑缺血模型KO小鼠显示显著的BBB的保护〔31〕，由此可以推测MMP-9对BBB的损伤引起HT。

3依达拉奉与rt-PA联合治疗急性脑梗死

如何安全有效地抑制MMP-9的生成及降低其水平成为了一个研究目标，了解到在缺血及再灌注损伤过程中，始终相关的一项作用因素即为氧化应激，产生大量炎症因子反应，生成大量自由基〔32〕及促进MMP-9水平升高〔33〕，导致血管神经单元损伤，破坏血脑屏障，甚至出血转化〔34〕。依达拉奉作为有效的脑保护剂应运而生。依达拉奉的获益首先在日本被报道〔35〕，1993年～2008年出版了Lapchak致力于药物的临床疗效和毒理学的文献评论的研究，证实依达拉奉的作用和应用前景〔36〕。2001年依达拉奉被日本卫生部、劳工与福利局认可作为自由基清除与神经保护剂，24 h内使用可以改善神经功能症状，日常生活能力及临床预后〔37〕，2009年写进卒中管理指南作为B级推荐，亦被美国心脏病学会(AHA)组织指南推荐为急性脑梗死早期用药。

依达拉奉是具有水和脂溶性属性的小分子基团，BBB的通透率是60%，静脉给药后静滴10 min达血药浓度，清除脑内具有高度细胞毒性的羟基基团〔38〕，可抑制脂质过氧化作用〔39〕，减轻脑缺血和脑缺血引起的脑水肿及组织损伤〔40〕，防止梗死灶扩大、减少迟发性脑细胞死亡〔41〕，改善神经功能〔42〕。rt-PA溶栓患者依达拉奉亦能降低血MMP-9浓度〔43〕，改善早期血管再通〔44〕，降低出溶栓后HT〔45〕，降低溶栓相关神经毒性作用〔46〕。

依达拉奉联合溶栓治疗首先由Yoshida等〔47〕提出，他们发现由溶栓治疗引起的出血性事件可能会被依达拉奉降低，因此他们认为治疗有助于减少卒中的死亡率和改善神经功能缺损。近期一项小鼠动物模型实验发现依达拉奉联合t-PA溶栓治疗起到协同作用、增进t-PA效果，减少HT，提高生存率，改善神经功能，增强再灌注〔48〕。研究发现rt-PA联合依达拉奉治疗发现能明显改善预后，随后Kono等〔49〕将研究扩大到129例亦发现同样效果，Wada等〔50〕认为依达拉奉联合rt-PA改善早期临床症状，有效改善血管再通和HT〔51〕,可作为预防HT用药。大型研究看出，联合依达拉奉的溶栓症状性出血率远远低于未联合依达拉奉者〔52～54〕。目前日本正在大规模开展YAMATO(the tPA and Edaravone Combination Therapy study—a multiple stroke center trial)研究，旨在发现溶栓同时使用依达拉奉使得再通率增高，减少出血并发症或者改善预后。

4总结与展望

依达拉奉能够有效安全的抑制MMP-9的水平，此前的研究大部分为溶栓后数小时后开始使用依达拉奉，而相关研究表明溶栓前或溶栓同时使用效果更佳，目前的资料尚少，待更多研究以便推广。

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〔2015-03-15修回〕

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