[转帖]The Molecular Biology of Cerebral Ischemia

作者：阿辽 标签：欢迎板砖

阅读次数：72

脑缺血的分子生物学 --王茜翻译

A particularly exciting dimension of cerebral ischemia research in the 1990s is the growing contribution of molecular biology, to both our understanding of the pathophysiology of isch-emic injury and the construction of novel ther-apeutic approaches. Space constraints permit only representative work to be cited. Recent observations have confirmed that ce-rebral ischemia gives rise to widespread alter-ations of gene regulation and expression. For example, ischemia leads to the rapid expression of immediate-early genes of the c-fos and c-jun
families, whose gene products interact to form fos-jun heterodimers that function as the so-called AP-1 transcription factor, regulating the expression of other genes. Focal ischemia trig-gers the prompt expression of c-fos and c-jun mRNA (54, 55), which peaks during early reperfusion, with 4- to 6-fold increases in AP-1
binding activity (54) (Fig 5). The latter may be suppressed in vivo by the intracerebroventricu-lar administration of antisense c-fos oligode-oxynucleotides (56). Cerebral ischemia and trauma also induce the expression of heat shock genes-so-called stress genes-in the brain (57). In focal cerebral ischemia, hsp70 mRNA is induced within 4 hours and persists for at least 24 hours. Inter-estingly, the hsp70 message is only patchily induced within the ischemic core but is mark-edly induced in neurons of the penumbra at 4 to 24 hours. Correspondingly, the strong expres-sion of hsp70 protein in neurons of the penum-.bra at 24 hours allows it to serve as a reliable anatomic marker of that zone (58). The study of ischemic mechanisms has been vastly abetted by the use of transgenic and knockout mouse mutants. The challenges im-posed by physiological monitoring, blood sam-pling, and implementation of ischemia models in these tiny animals have been largely sur-mounted (59). There are several elegant exam-ples of the use of transgenic and knockout mu-tant mice to establish the relevance of specific
stroke mechanisms. For example, studies in transgenic mice with threefold overexpression of the enzyme CuZn superoxide dismutase have convincingly established the role of oxygen rad-ical scavenging in diminishing neural injury af-ter transient focal ischemia (60). In other stud-ies of mutant (knockout) mice that fail to express the neuronal isoform of nitric oxide syn-thase (NOS), smaller infarcts develop and the mice have less severe neurologic deficits than normal mice (61). In contrast, knockout mice deficient in the endothelial form of NOS have larger infarcts than normal (62). Studies such as these have provided definitive answers to challenging mechanistic questions. Therapeutically, there are already intriguing examples of targeted molecular-biological ap-proaches to treatment of ischemia. Thus, anti-sense oligodeoxynucleotides to the NMDA-R1 component of the NMDA receptor channel complex, when given to rats with MCA occlu-sion, reduce the volume of ischemic infarction (63). In other studies, viral vectors have been used to introduce "therapeutic" genes into the
central nervous system. Thus, overexpression of the glucose transporter gene via the introduc-tion of a herpes simplex viral vector into the nervous system protected neurons from focal ischemic injury (64). In another study, the use of an adenoviral vector to induce central ner-vous system overexpression of receptor antag-onist
protein to the damaging cytokine, inter-leukin- 1, led to reduction in stroke size (65). These studies are vanguard examples of what, in future years, might evolve into accepted ther-apeutic strategies!
二十世纪九十年代的脑缺血研究中尤其另人兴奋的一个方面就是分子生物学，它极大地补充了我们对缺血损伤的病理了解，也补充了独创的治疗方法。由于篇幅所限，我只能引述一些很有代表性的研究。
最近的研究证实，脑缺血导致基因表达与调控的大范围改变。例如，缺血导致c-fos和c-jun家族即刻早期基因的迅速表达，这些家族的基因产物相互作用以形成fos-jun异质二聚体，这种聚体发挥所谓的AP-1转录因子的作用，调节其他基因的表达。局部缺血引起c-fos和c-jun mRNA(54,55)的即时表达,这种表达在早期再灌注时达到顶点，在AP-1黏着运动中增加了4到6倍（54）（图5）。在活体内，后者可能会被antisense c-fos oligodeoxynucleotide(56)的脑室内给药所压抑。
脑缺血和外伤也会引起热休克基因--也叫压力基因--在脑中的表达（57）。在局部脑缺血中，hsp70 m RNA在四小时内被注入，持续至少24小时。有趣的是，hsp70信息在缺血核心部位仅是被不规则地导入了，却在4到24小时内明显地被导入了半暗带的神经元。相应地，在24小时内半暗带神经元内的hsp70蛋白质的强烈表达使得它可以被作为那个区域的可靠的解剖学标记（58）。
转基因和被击昏的老鼠突变体的使用极大地支持了对缺血机械的研究。生理监护，取血样，以及在这些小动物身上植入缺血模型，这一系列难度很大的工作（59）都已经在很大程度上得到了实现。有很多利用转基因和被击昏的突变老鼠的试验都证明了具体的中风机理。例如，研究人员曾经对有三倍酶CuZn超氧化物歧化酶过多表达的转基因老鼠进行过研究，有力地树立了氧原子团净化在短暂局部缺血后消除神经损伤的作用（60）。其他一些研究变异（被击昏的）老鼠的试验没有能够表达一氧化氮合酶（NOS）的神经元对碘氧基苯甲醚，但是出现的梗死梗小，而且与正常的老鼠相比，老鼠的神经学缺陷也不那么严重（61）。相反，NOS内皮组织不足的被击昏的老鼠比正常老鼠的梗塞要大（62）。这类研究都已经为具有挑战性的机制问题提供了权威性的答案。
在治疗学方面，早已经有很多目的性很强的应用分子-生物学方法治疗缺血的例子。因而antisense oligodeoxynucleotides到NMDA受体渠道联合体的MNDA-R1组成，当把它们被种入MCA闭塞的老鼠身上的时候，可减少缺血梗塞形成量（63）。在其他的研究中，研究人员用携带腺病毒载体把"治疗"基因带入中枢神经系统。这样，葡萄糖载体基因的过度表达通过疱疹单一腺病毒载体进入到神经系统，保护神经元不受局部缺血损伤（64）。在另一项研究中，研究人员使用腺腺病毒载体将中枢神经系统受体拮抗体蛋白的过度表达诱导入具有破坏性的cytokine和白细胞间介素-1中，使得中风区域减少（65）。这些研究极为前瞻，将来会发展为被大家广为认可的治疗手段！
(来自英语听力特快)