Institut de Biologie du Développement de Marseille-Luminy (IBDML), UMR6216 (Centre National de la Recherche Scientifique/Université de la Méditerranée), Marseille, France.
PLoS One. 2010 Jan 1;5(1):e8550. doi: 10.1371/journal.pone.0008550.
Ciliary neurotrophic factor (CNTF) is a potent neuroprotective cytokine in different animal models of glutamate-induced excitotoxicity, although its action mechanisms are still poorly characterized. We tested the hypothesis that an increased function of glial glutamate transporters (GTs) could underlie CNTF-mediated neuroprotection. We show that neuronal loss induced by in vivo striatal injection of the excitotoxin quinolinic acid (QA) was significantly reduced (by approximately 75%) in CNTF-treated animals. In striatal slices, acute QA application dramatically inhibited corticostriatal field potentials (FPs), whose recovery was significantly higher in CNTF rats compared to controls (approximately 40% vs. approximately 7%), confirming an enhanced resistance to excitotoxicity. The GT inhibitor DL-threo-beta-benzyloxyaspartate greatly reduced FP recovery in CNTF rats, supporting the role of GT in CNTF-mediated neuroprotection. Whole-cell patch-clamp recordings from striatal medium spiny neurons showed no alteration of basic properties of striatal glutamatergic transmission in CNTF animals, but the increased effect of a low-affinity competitive glutamate receptor antagonist (gamma-D-glutamylglycine) also suggested an enhanced GT function. These data strongly support our hypothesis that CNTF is neuroprotective via an increased function of glial GTs, and further confirms the therapeutic potential of CNTF for the clinical treatment of progressive neurodegenerative diseases involving glutamate overflow.
睫状神经营养因子（CNTF）是不同谷氨酸诱导兴奋毒性动物模型中一种有效的神经保护细胞因子，尽管其作用机制仍不清楚。我们测试了这样一种假设，即神经胶质细胞谷氨酸转运体（GTs）的功能增强可能是 CNTF 介导的神经保护的基础。我们发现，体内纹状体注射兴奋毒素喹啉酸（QA）诱导的神经元丢失在 CNTF 处理的动物中显著减少（约 75%）。在纹状体切片中，急性 QA 应用显著抑制皮质纹状体场电位（FPs），而 CNTF 大鼠的 FP 恢复明显高于对照组（约 40%对约 7%），证实了对兴奋毒性的增强抵抗。GT 抑制剂 DL-threo-beta-苯甲氧基天冬氨酸大大降低了 CNTF 大鼠中的 FP 恢复，支持 GT 在 CNTF 介导的神经保护中的作用。来自纹状体中间神经元的全细胞膜片钳记录显示，CNTF 动物纹状体内谷氨酸能传递的基本特性没有改变，但低亲和力竞争性谷氨酸受体拮抗剂（γ-D-谷氨酰甘氨酸）的作用增强也表明 GT 功能增强。这些数据强烈支持我们的假设，即 CNTF 通过增强神经胶质细胞 GT 的功能来发挥神经保护作用，并进一步证实了 CNTF 在治疗涉及谷氨酸溢出的进行性神经退行性疾病方面的治疗潜力。
