Auer R N
Department of Pathology, University of Calgary, Faculty of Medicine, Alberta.
Neurotoxicology. 1991 Fall;12(3):541-6.
Initial research by Olney, investigating the toxicity of glutamate as a food additive, demonstrated that irreversible (necrotic) changes could be produced in the CNS by glutamate. Subsequently, it became clear that the release of excitatory amino acids into the extracellular space of nervous tissue may play a role in CNS ischemia, and, later hypoglycemia. Experiments utilizing excitatory amino acid antagonists at the N-methyl-d-aspartate and other subtypes of excitatory receptor have shown neuronal protection, in both ischemia and hypoglycemia. The protection is robust enough to produce a detectable improvement in neurologic deficit on neurobehavioral testing, in addition to significantly reducing the number of necrotic cells in the brain. A third condition where excitotoxicity plays a role is toxic mussel poisoning. In contrast to ischemia and hypoglycemia, an excitotoxin which is exogenous to the brain plays a role. Domoic acid is contained in mussels which have filter-fed large quantities of domoate-rich phytoplankton, and when contaminated mussels are ingested in large quantities, serious and irreversible CNS effects, accompanied by necrosis, may result. In contrast to ischemia and hypoglycemia, however, damage is mediated at a different excitatory CNS receptor, namely the kainate receptor. In all three conditions, a constant aspect of the excitotoxic pathology is an increased susceptibility to excitotoxic damage with increasing age. This may be due to the dendritic location of excitatory receptors, and the richer branching of neuronal dendritic trees in aged animals, leading to enhanced susceptibility of the neuron to excitotoxic necrosis with age.
奥尔尼最初研究谷氨酸作为食品添加剂的毒性时发现，谷氨酸可在中枢神经系统产生不可逆（坏死性）变化。随后，人们清楚地认识到，兴奋性氨基酸释放到神经组织细胞外间隙可能在中枢神经系统缺血以及后来发现的低血糖过程中发挥作用。利用N-甲基-D-天冬氨酸和其他兴奋性受体亚型的兴奋性氨基酸拮抗剂进行的实验表明，在缺血和低血糖情况下均有神经元保护作用。这种保护作用足够强大，除了能显著减少脑中坏死细胞数量外，还能在神经行为测试中使神经功能缺损得到可检测到的改善。兴奋性毒性起作用的第三种情况是有毒贻贝中毒。与缺血和低血糖不同，这里起作用的是一种脑外源性兴奋性毒素。软骨藻酸存在于滤食了大量富含软骨藻酸盐浮游植物的贻贝中，大量食用受污染贻贝可能导致严重且不可逆的中枢神经系统效应，并伴有坏死。然而，与缺血和低血糖不同的是，损伤是通过不同的中枢神经系统兴奋性受体，即 kainate 受体介导的。在所有这三种情况下，兴奋性毒性病理的一个不变特征是随着年龄增长对兴奋性毒性损伤的易感性增加。这可能是由于兴奋性受体位于树突上，且老年动物神经元树突分支更丰富，导致神经元随年龄增长对兴奋性毒性坏死的易感性增强。
