Brain tissue responses to ischemia
Brain tissue responses to ischemia
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DOI：
10.1172/jci11003
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发表时间：
2000-09-01
影响因子：
15.9
通讯作者：
Choi, DW
中科院分区：
文献类型：
--
作者：
Lee, JM;Grabb, MC;Choi, DW
组织对缺血流入神经元的反应。谷氨酸受体激活通道的门控有效地实现了膜分流，这种分流从缺血核心向缺血区边缘（缺血半暗带）呈波状扩散（扩张性抑制）。扩散性抑郁增加代谢需求和能量衰竭，从而进一步促进谷氨酸释放。当Na+和Ca2+的进入伴随着cl和水的流入时，出现明显的神经元细胞体肿胀和树突肿胀，这是坏死死亡的标志。神经元胞内游离Ca2+([Ca2+] i)的升高，直接由NMDA受体介导，间接通过膜去极化激活的电压限制Ca2+通道和Na+-Ca2+交换器的反向操作，对促进扩散性抑郁和触发有害的细胞毒性级联负有特殊的责任。在神经元细胞培养中，选择性NMDA受体阻断可阻止大部分Ca2+内流和短暂的谷氨酸暴露引起的细胞死亡(1)。NMDA拮抗剂还能显著减轻氧和/或葡萄糖剥夺诱导的培养神经元的死亡，这一观察结果与选择性激动剂的研究结果非常吻合。暴露于NMDA仅需3-5分钟就足以引发广泛培养的皮质神经元死亡（“快速触发兴奋性毒性”），而暴露于饱和浓度的海碱盐通常需要数小时才能达到同样的效果（“缓慢触发兴奋性毒性”）。与由AMPA或kainate受体激活的电压门控通道和交换途径介导的Ca2+内流速率较慢相比，这种时间过程的差异与NMDA受体门控通道直接介导的Ca2+内流速率较高相匹配。NMDA受体拮抗剂在局灶性脑缺血、低血糖或创伤的动物模型中也具有高度的神经保护作用(2)，尽管不是短暂的全脑缺血(3)。在后一种情况下，NMDA受体介导的兴奋性毒性在诱导致死性神经元损伤方面可能不如AMPA受体促进的Zn2+进入那么突出（见下文）。这种显著变化的原因目前还没有明确的定义，但一个促成因素可能是由于整体缺血期间乳酸积累引起的细胞外酸度，这一事件在局部缺血的半暗区不那么突出，因为灌注是部分维持的。这种酸转移选择性下调NMDA受体和NMDA受体介导的兴奋性毒性，但增强AMPA受体介导的兴奋性毒性(4)；它也可能促进有毒的Zn2+通过电压门控Ca2+通道进入(5)。
Tissue responses to ischemia influx into neurons. The gating of glutamate receptor–activated channels effectively achieves membrane shunting, which spreads in waves (spreading depression) from the ischemic core out toward the margins of the ischemic zone (ischemic penumbra). Spreading depression increases metabolic demand and energy failure, thus further enhancing glutamate release. Marked neuronal cell body swelling and dendrite swelling occur, hallmarks of necrosis death, as Na+ and Ca2+ entry is joined by the influx of Cl–and water. Elevations in neuronal intracellular free Ca2+([Ca2+] i), mediated both directly by NMDA receptors and indirectly via membrane depolarization–activated voltagegated Ca2+ channels and reverse operation of the Na+-Ca2+ exchanger, bear particular responsibility for promoting spreading depression and triggering deleterious cytotoxic cascades. In neuronal cell cultures, selective NMDA receptor blockade prevents most of the Ca2+ influx and cell death induced by brief intense glutamate exposures (1). NMDA antagonists also markedly attenuated the death of cultured neurons induced by oxygen and/or glucose deprivation, observations that fit well with studies conducted with selective agonists. Exposure to NMDA for as little as 3–5 minutes is sufficient to trigger widespread cultured cortical neuronal death (“rapidly triggered excitotoxicity”), whereas exposure to even saturating concentrations of kainate typically requires hours to do the same (“slowly triggered excitotoxicity”). This difference in time course fits with a higher rate of Ca2+ influx mediated directly by NMDA receptor–gated channels, compared with a slower rate of Ca2+ influx mediated by the voltage-gated channel and exchanger routes activated by AMPA or kainate receptors. NMDA receptor antagonists are also highly neuroprotective in animal models of focal brain ischemia, as well as hypoglycemia or trauma (2), although not transient global ischemia (3). In this latter setting, NMDA receptor–mediated excitotoxicity may be less prominent than AMPA receptor–facilitated Zn2+ entry in inducing lethal neuronal injury (see below). Reasons for this shift in prominence are presently not welldefined, but a contributing factor may be extracellular acidity due to accumulation of lactic acid during global ischemia, an event less prominent in the penumbra of focal ischemia where perfusion is partially maintained. This acid shift selectively downregulates NMDA receptors and NMDA receptor–mediated excitotoxicity but enhances AMPA receptor–mediated excitotoxicity (4); it may also enhance toxic Zn2+ entry through voltage-gated Ca2+ channels (5).