Department of Biomedical Sciences, Marquette University, 561 N. 15th Street, Room 426, Milwaukee, WI 53233, United States.
Department of Biomedical Sciences, Marquette University, 561 N. 15th Street, Room 426, Milwaukee, WI 53233, United States.
Brain Res. 2014 Feb 14;1547:25-33. doi: 10.1016/j.brainres.2013.12.018. Epub 2013 Dec 25.
The cystine/glutamate antiporter (system xc-) transports cystine into cell in exchange for glutamate. Fibroblast growth factor-2 (FGF-2) upregulates system xc- selectively on astrocytes, which leads to increased cystine uptake, the substrate for glutathione production, and increased glutamate release. While increased intracellular glutathione can limit oxidative stress, the increased glutamate release can potentially lead to excitotoxicity to neurons. To test this hypothesis, mixed neuronal and glial cortical cultures were treated with FGF-2. Treatment with FGF-2 for 48 h caused a significant neuronal death in these cultures. Cell death was not observed in neuronal-enriched cultures, or astrocyte-enriched cultures, suggesting the toxicity was the result of neuron-glia interaction. Blocking system xc- eliminated the neuronal death as did the AMPA/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), but not the NMDA receptor antagonist memantine. When cultures were exposed directly to glutamate, both NBQX and memantine blocked the neuronal toxicity. The mechanism of this altered profile of glutamate receptor mediated toxicity by FGF-2 is unclear. The selective calcium permeable AMPA receptor antagonist 1-naphthyl acetyl spermine (NASPM) failed to offer protection. The most likely explanation for the results is that 48 h FGF-2 treatment induces AMPA/kainate receptor toxicity through increased system xc- function resulting in increased release of glutamate. At the same time, FGF-2 alters the sensitivity of the neurons to glutamate toxicity in a manner that promotes selective AMPA/kainate receptor mediated toxicity.
胱氨酸/谷氨酸反向转运体（系统 xc-）将胱氨酸转运到细胞内，以交换谷氨酸。成纤维细胞生长因子-2（FGF-2）选择性地上调星形胶质细胞中的系统 xc-，导致胱氨酸摄取增加，这是谷胱甘肽产生的底物，并增加谷氨酸释放。虽然增加细胞内谷胱甘肽可以限制氧化应激，但增加的谷氨酸释放可能导致神经元的兴奋性毒性。为了验证这一假设，用 FGF-2 处理混合神经元和神经胶质皮质培养物。用 FGF-2 处理 48 小时会导致这些培养物中的神经元明显死亡。在神经元富集培养物或星形胶质细胞富集培养物中未观察到细胞死亡，这表明毒性是神经元-胶质相互作用的结果。阻断系统 xc-消除了神经元死亡，如 AMPA/KA 受体拮抗剂 2,3-二羟基-6-硝基-7-磺胺基苯并[f]喹喔啉-2,3-二酮（NBQX）和 NMDA 受体拮抗剂美金刚胺（memantine）。当培养物直接暴露于谷氨酸时，NBQX 和 memantine 均可阻断神经元毒性。FGF-2 引起的这种改变的谷氨酸受体介导毒性的机制尚不清楚。选择性钙通透性 AMPA 受体拮抗剂 1-萘乙酰基 spermine（NASPM）未能提供保护。最可能的解释是，48 小时 FGF-2 处理通过增加系统 xc-功能诱导 AMPA/KA 受体毒性，导致谷氨酸释放增加。同时，FGF-2 改变了神经元对谷氨酸毒性的敏感性，促进了选择性 AMPA/KA 受体介导的毒性。
