Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis.
Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis.
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DOI：
10.1089/neu.1995.12.943
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发表时间：
1995-10
影响因子：
4.2
通讯作者：
B. Siesjö;Ken-ichiro Katsura;Qi Zhao;J. Folbergrová;Kerstin Pahlmark;Peter Siesjö;Maj-lis Smith
中科院分区：
文献类型：
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作者：
B. Siesjö;Ken-ichiro Katsura;Qi Zhao;J. Folbergrová;Kerstin Pahlmark;Peter Siesjö;Maj-lis Smith
这篇文章的目的是合并以前的结果到一个投机性的合成，揭示了继发性脑损伤的原因，无论是全球/前脑或局灶性缺血。该假说是基于一个有充分根据的假设，即全脑或前脑缺血引起的脑损伤的病理生理学不同于局灶性缺血。在前者中，缺血通常是密集的且持续时间短，并且如果再灌注是充分的，则细胞损伤显著延迟，主要影响选择性脆弱的神经元。相比之下，局灶性缺血要么是持久的，要么是永久的，而且通常不太严重，特别是在局灶周围半影区域。病变通常是泛坏死性的（“梗死”），最初影响闭塞动脉供血的病灶，随后侵入半暗带区。现有的结果允许重申的钙假说的细胞死亡。在全脑或前脑缺血中，设想通过由电压或谷氨酸受体门控的通道的钙内流触发限制再灌注期间神经元存活的反应，导致存活数小时或数天后的继发性神经元死亡。可以假设，初始损伤导致膜钙处理的持续改变，导致线粒体缓慢、逐渐的钙超载。或者，细胞内信号转导途径的持续扰动导致转录或翻译的变化，使细胞丧失热休克和应激蛋白、营养因子或存活所需的酶。然而，除了沙鼠可能的例外，微血管衰竭和原发性线粒体功能障碍都不被认为是相关的。在局灶性缺血中，类似的反应可能是由钙内流触发的，无论是持续性的（病灶）还是间歇性的（半影）。然而，这些在细胞死亡中起次要作用，因为它们被产生迅速发展的继发性损伤的介质的反应所覆盖，影响微血管或线粒体。很可能，这些介质中的一些是自由基，或一氧化氮，或其他活性代谢物，从脂质水解和花生四烯酸代谢产生。在连续缺血期间，或在缺血1-3小时后的再循环期间，这些介质激活内皮细胞或多形核白细胞中的粘附分子，或氧化关键蛋白质。其结果是微循环的失败（“毛细血管堵塞”），或持续的线粒体衰竭。由于钙内流是一个初始事件，减少突触前去极化和钙进入谷氨酸受体门控和其他钙通道的药物具有可预见的狭窄的治疗窗口;然而，由于硝酮类的自旋捕获剂在诱导局灶性缺血后许多小时起作用，它们的治疗窗口可能非常宽。这可能是因为粘附分子的mRNA表达及其合成是相对缓慢的过程，并且因为硝酮作用于涉及白细胞粘附到内皮细胞的事件，伴随毛细血管和毛细血管后小静脉的堵塞，以及随后的炎症反应。
The objective of this article is to amalgamate previous results into a speculative synthesis that sheds light on the causes of secondary brain damage following either global/forebrain or focal ischemia. The hypothesis is based on the well-founded assumption that the pathophysiology of the brain damage incurred by global or forebrain ischemia is different from that of focal ischemia. In the former, the ischemia is usually dense and of brief duration and, provided that reperfusion is adequate, cell damage is conspicuously delayed, mostly affecting selectively vulnerable neurons. In contrast, focal ischemia is either long-lasting or permanent, and it is usually less severe, particularly in the perifocal penumbral regions. The lesion is typically pan-necrotic ("infarction"), initially affecting the focus supplied by the occluded artery, later invading the penumbra zone. Available results allow a restatement of the calcium hypothesis of cell death. In global or forebrain ischemia, calcium influx through channels gated by voltage or glutamate receptors is envisaged to trigger reactions that limit the survival of neurons during reperfusion, leading to secondary neuronal death after hours or days of survival. It can be hypothesized that the initial insult leads to a sustained alteration of membrane calcium handling, resulting in slow, gradual calcium overload of mitochondria. Alternatively, a sustained perturbation of the intracellular signal transduction pathway leads to changes in transcription or translation, bereaving the cells of heat shock and stress proteins, of trophic factors, or of enzymes required for survival. However, with the possible exception of the gerbil, neither microvascular failure nor primary mitochondrial dysfunction is believed to be involved. In focal ischemia, similar reactions are probably triggered by calcium influx, whether this is sustained (the focus) or intermittent (the penumbra). However, these play a minor role in cell death since they are overridden by reactions producing mediators of rapidly developing secondary damage, affecting either microvessels or mitochondria. Very probably, some of these mediators are free radicals, or nitric oxide, or other reactive metabolites, emanating from lipid hydrolysis and arachidonic acid metabolism. During continuous ischemia, or during recirculation following 1-3 h of ischemia, these mediators activate adhesion molecules in endothelial cells or polymorphonuclear leucocytes, or oxidize key proteins. The result is either failure of microcirculation ("capillary plugging"), or sustained mitochondrial failure. Since calcium influx is an initial event, agents reducing presynaptic depolarization and calcium entry through glutamate receptor-gated and other calcium channels have predictably a narrow therapeutic window; however, since spin trapping agents of the nitrone class act many hours after the induction of focal ischemia, their therapeutic window is potentially very wide. This may be because expression of mRNAs for adhesion molecules and their synthesis are relatively slow processes, and because the nitrones act on events that involve adhesion of leukocytes to the endothelial cells, with plugging of capillaries and postcapillary venules, and on the ensuing inflammatory response.