Puka-Sundvall M, Eriksson P, Nilsson M, Sandberg M, Lehmann A
Department of Anatomy and Cell Biology, University of Göteborg, Sweden.
Brain Res. 1995 Dec 24;705(1-2):65-70. doi: 10.1016/0006-8993(95)01139-0.
L-Cysteine produces excitotoxic brain damage but its chemical structure differs from that of other excitotoxins. Although it is an NMDAmimetic, its mode of action is complex and may encompass antiexcitotoxic components. The purpose of the present study was to investigate whether cysteine kills neurons by potentiating the effects of glutamate and/or by releasing glutamate. In primary cultures of cortical neurons, 24 h of exposure to glutamate caused a concentration-dependent, dizocilpine-sensitive cell death as measured by release of lactate dehydrogenase. Cysteine was also toxic but higher concentrations were required. In addition, N-acetylcysteine produced mild toxicity at 1 mM. There was no general potentiation between either glutamate and cysteine or glutamate and N-acetylcysteine although some combinations acted synergistically. In no case did the thiols inhibit glutamate toxicity. The interaction between glutamate and cysteine toxicity was also assessed in the immature rat arcuate nucleus in vivo. When given at a dose (0.5 mg/g) that did not cause any toxicity per se, cysteine enhanced the toxicity of glutamate (0.3-0.8 mg/g). Cortical microdialysis was carried out in anesthetized rats (8-10 days old) administered a toxic dose of cysteine (1 mg/g). The levels of taurine were elevated 15-fold, phosphoethanolamine 3-fold and alanine 2-fold. Despite the observation that glutamine decreased markedly and rapidly, there was only a delayed doubling of glutamate concentrations. It is therefore unlikely that cysteine induces neurotoxicity by releasing glutamate. Taken together, the results suggest that there is a synergistic effect between cysteine and glutamate. Speculatively, this potentiation may be produced by reduction by cysteine of the redox site of the glutamate-activated NMDA receptor-ionophore complex.
L-半胱氨酸会导致兴奋性毒性脑损伤，但其化学结构与其他兴奋性毒素不同。尽管它是一种N-甲基-D-天冬氨酸（NMDA）模拟物，但其作用模式复杂，可能包含抗兴奋性毒性成分。本研究的目的是调查半胱氨酸是否通过增强谷氨酸的作用和/或通过释放谷氨酸来杀死神经元。在皮质神经元的原代培养物中，暴露于谷氨酸24小时会导致浓度依赖性的、对地卓西平敏感的细胞死亡，这通过乳酸脱氢酶的释放来衡量。半胱氨酸也具有毒性，但需要更高的浓度。此外，N-乙酰半胱氨酸在1 mM时产生轻度毒性。谷氨酸与半胱氨酸或谷氨酸与N-乙酰半胱氨酸之间不存在普遍的增强作用，尽管某些组合具有协同作用。在任何情况下，硫醇都不会抑制谷氨酸毒性。还在未成熟大鼠的弓状核体内评估了谷氨酸和半胱氨酸毒性之间的相互作用。当以本身不会引起任何毒性的剂量（0.5 mg/g）给予半胱氨酸时，它会增强谷氨酸（0.3 - 0.8 mg/g）的毒性。在给予毒性剂量半胱氨酸（1 mg/g）的麻醉大鼠（8 - 10日龄）中进行皮质微透析。牛磺酸水平升高了15倍，磷酸乙醇胺升高了3倍，丙氨酸升高了2倍。尽管观察到谷氨酰胺明显且迅速下降，但谷氨酸浓度仅延迟翻倍。因此，半胱氨酸不太可能通过释放谷氨酸来诱导神经毒性。综上所述，结果表明半胱氨酸和谷氨酸之间存在协同作用。推测这种增强作用可能是由于半胱氨酸对谷氨酸激活的NMDA受体 - 离子通道复合物的氧化还原位点的还原作用所致。
