Cellular mechanisms underlying excitotoxicity
Cellular mechanisms underlying excitotoxicity
复制标题
兴奋性毒性的细胞机制
DOI：
10.1016/0166-2236(87)90023-3
复制
发表时间：
1987
影响因子：
15.9
通讯作者：
G. Westbrook
中科院分区：
文献类型：
--
作者：
M. Mayer;G. Westbrook
合适的治疗方案。重要的问题似乎是：(1) 阐明个体兴奋性氨基酸受体亚型在特定病理生理学模型中的作用；(2) 确定与每种受体亚型激活相关的离子通量，以及这些受体亚型对神经元损伤的细胞后果；(3) 评估兴奋性氨基酸受体激活的继发过程对兴奋性毒性过程的贡献程度：这些包括在初始兴奋作用之后 L-谷氨酸的进一步突触释放。氨基酸，或钾流出到细胞外液后递质释放按钮的去极化，使得L-谷氨酸的释放从细流变成洪流；通过上述机制释放其他非氨基酸递质可能有助于兴奋性毒性过程； (4)了解不同的激发模式是否有助于氨基酸作为兴奋毒素的效力。各个酸性氨基酸的兴奋作用非常具有特征性——NMDA 受体偏好的激动剂会引起动作电位的爆发性放电，而红藻氨酸会引起非脱敏，因此持久的去极化，与膜电阻的急剧下降以及由于钠通道失活而导致动作电位机制的丧失相关。关于上述机制的重要性，我们现在有很多线索。对多种制剂的生理实验表明，兴奋性氨基酸可激活可渗透 Na+ 和 K+ 的非选择性阳离子通道 1-4。显然，兴奋性氨基酸（尤其是红藻氨酸）的急性施用将产生大量离子通量，主要是Na+离子通过受体门控离子通道流入，以及K+通过这些相同通道和电压激活钾通道流出。伴随这些离子通量的是 C1 分子和水分子被动运动到神经元中。在两种分离的制剂中，即大鼠胎儿海马 a 和体外鸡视网膜 6 的培养物，来自离子替代实验的实验证据表明，神经细胞膜的渗透破坏是 L-谷氨酸和红藻氨酸通过递质诱导的离子流引起的肿胀而产生急性兴奋性毒性作用的基础。用不可渗透的阴离子取代细胞外的 C1-，或用不可渗透的阳离子取代细胞外的 Na+，可以使这些分离制剂中的神经元免于兴奋性氨基酸诱发的细胞死亡。红藻氨酸应该具有特别的兴奋毒性，这得到了对分离制剂（来自金鱼视网膜 7 的新鲜分离的水平细胞和来自幼鼠的海马神经元）的生理实验的支持。在这些制剂中的每一种中，通过快速灌注技术以已知浓度的兴奋性氨基酸的浴应用用于研究电压钳下的脱敏。虽然这两种制剂均不对 NMDA 产生反应，但红藻氨酸在引起非脱敏反应方面具有独特性；在培养小鼠脊髓神经元的实验中也获得了类似的结果（Westbrook，GL，未发表的观察结果）。因此，与 L-谷氨酸盐相比，红藻氨酸盐产生渗透破坏性离子流的时间要长得多。体内细胞摄取机制限制了某些氨基酸在神经纤维内的扩散，这必定是决定这些药物作为兴奋性毒素的效力的一个因素；红藻氨酸 9 缺乏高亲和力摄取机制肯定也导致了其作为兴奋性毒素的高效力。此外，特别高的灵敏度......
suitable treatment protocols. The important issues would seem to be:(1) elucidating the role of individual excitatory amino acidreceptor subtypes in specific pathophysiological models;(2) determining the ion fluxes associated with activation of each receptor subtype, and the cellular consequences these have for neuronal damage;(3) evaluating the degree to which processes secondary to activation of excitatory amino acid receptors contribute to the excitotoxic process: these include further synaptic release of L-glutamate subsequent to either the initial excitatory action of amino acids, or to depolarization of transmitter-releasing boutons following effiux of potassium into the extracellular fluid, such that the release of L-glutamate changes from a trickle to a torrent; the release of other non-amino acid transmitters via the above mechanisms could conceivably contribute to the excitotoxic process; and (4) knowing whether different firing patterns contribute to the potency of amino acids as excitotoxins. The excitatory action of individual acidic amino acids is quite characteristic-NMDA-receptor-preferring agonists evoke a burst discharge of action potentials, whereas kainic acid evokes a nondesensitizing, and therefore longlasting depolarization, associated with a precipitous fall in membrane resistance, and a loss of the action potential mechanism due to sodium channel inactivation. We now have many clues as to the importance of the above mechanisms. Physiological experiments on a variety of preparations show that excitatory amino acids activate non-selective cationic channels 1-4 permeable to both Na+ and K+. Clearly the acute administration of excitatory amino acids, especially kainic acid, will generate large ionic fluxes, prinicipally influx of Na+ ions through receptor-gated ion channels, and efflux of K+ through these same channels and through voltage-activated potassium channels. Accompanying these ionic fluxes will be the passive movement of C1-and water molecules into the neuron. In two isolated preparations, cultures of rat fetal hippocampus a, and in-vitro chick retina 6, experimental evidence from ion substitution experiments suggests that osmotic disruption of the nerve cell membrane underlies the acute excitotoxic action of L-glutamate and kainic acid, via swelling due to transmitter-induced ion fluxes. Replacement of extracellular C1-with impermeable anions, or replacement of extracellular Na+ with impermeable cations, spares neurons in these isolated preparations from excitatory amino acid-evoked cell death.That kainic acid should be especially excitotoxic is supported by physiological experiments also on isolated preparations-freshly dissociated horizontal cells from goldfish retina 7, and hippocampal neurons from young rats s. In each of these preparations, bath application of excitatory amino acids at known concentration via a rapid perfusion technique was used to study desensitization under voltage clamp. Although neither preparation responded to NMDA, kainic acid was unique in evoking nondesensitizing responseT'S; similar results have also been obtained in experiments on mouse spinal cord neurons in culture (Westbrook, GL, unpublished observations). Thus, compared to L-glutamate, for example, kainate generates osmotically disruptive ion fluxes for a far longer period. In-vivo cellular uptake mechanisms limit the diffusion of certain amino acids within the neuropil, and this must be a factor in determining the potency of these agents as excitotoxins; the absence of a high-affinity uptake mechanism for kainic acid 9 must certainly also contribute to its high potency as an excitotoxin. Furthermore, the especially high sensitivity of …