High extracellular glutamate and neuronal death in neurological disorders - Cause, contribution or consequence?
High extracellular glutamate and neuronal death in neurological disorders - Cause, contribution or consequence?
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DOI：
10.1111/j.1749-6632.1999.tb08004.x
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Obrenovitch, TP
中科院分区：
文献类型：
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作者：
Obrenovitch, TP
在神经系统疾病模型中，细胞外谷氨酸增加和谷氨酸受体拮抗剂产生的有益作用一直被视为兴奋性毒性的支持证据。这种系统性解释过于简单，可能会产生误导。高细胞外谷氨酸不是内源性兴奋毒性的可靠指标，即，当内源性谷氨酸在细胞外积累时，内源性谷氨酸的内在的、潜在的神经毒性。首先，因为在体内产生去极化和死亡所必需的谷氨酸的细胞外水平远高于在神经障碍模型中测量的水平。其次，因为突触间隙中谷氨酸浓度的变化（即，谷氨酸受体拮抗剂的保护作用并不必然意味着抑制兴奋性毒性异常。事实上，由损伤如缺血引起的神经元死亡是由可能相互关联的多因素过程引起的。因此，与谷氨酸介导的传递相互作用产生的有益作用实际上可能使细胞对其他有害机制（例如，线粒体损伤、氧化应激）更具抗性。
In models of neurological disorders, increased extracellular glutamate and beneficial effects produced by glutamate-receptor antagonists are consistently taken as supporting evidence of excitotoxicity. This systematic interpretation is over-simplified and potentially misleading.High extracellular glutamate is not a reliable indicator of endogenous excitotoxicity, i.e., the intrinsic, potential neurotoxicity of endogenous glutamate whenever it accumulates extracellularly, Firstly, because the extracellular levels of glutamate necessary to produce depolarization and death in vivo, are far above those measured in models of neurological disorders. Secondly, because changes in the concentration of glutamate in the synaptic cleft (i.e., the relevant compartment for endogenous excitotoxicity) are not reflected extracellularly.Protection by glutamate-receptor antagonists does not necessarily imply inhibition of excitotoxic abnormalities, Indeed, neuronal death initiated by insults such as ischemia results from multifactorial processes that may be interrelated. Therefore, beneficial effects resulting from an interaction with glutamate-mediated transmission may actually render the cell more resistant to other deleterious mechanisms (e.g,, mitochondrial injury, oxidative stress).