Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes
Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes
复制标题
DOI：
10.1074/jbc.m707697200
复制
发表时间：
2008-05-09
影响因子：
4.8
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
--
作者：
Lee, Seok-Geun;Su, Zhao-Zhong;Fisher, Paul B.
谷氨酸是调节大脑功能的重要神经递质。兴奋性氨基酸转运体（EAAT）-2是主要表达于星形胶质细胞的谷氨酸转运体之一。EAAT 2的功能障碍涉及急性和慢性神经系统疾病，包括中风/缺血、颞叶癫痫、肌萎缩性侧索硬化、阿尔茨海默病、人类免疫缺陷病毒1相关性痴呆和恶性神经胶质瘤的生长。头孢曲松，β-内酰胺类抗生素之一，是EAAT 2表达的刺激剂，在体外和体内模型中具有神经保护作用，部分基于其抑制谷氨酸兴奋性毒性引起的神经元细胞死亡的能力。基于这一考虑及其无毒性，头孢曲松具有操纵谷氨酸传递和改善神经毒性的潜力。我们研究了头孢曲松增强原代人胎儿星形胶质细胞（PHFA）中EAAT 2表达的机制。头孢曲松通过核因子-κ B（NF-κ B）信号通路提高PHFA中EAAT 2的转录。抗生素促进p65核转位和NF-κ B活化。EAAT 2启动子-272位的特异性NF-κ B结合位点负责头孢曲松介导的EAAT 2诱导。此外，头孢曲松增加谷氨酸摄取，EAAT 2的主要功能，和EAAT 2小干扰RNA完全抑制头孢曲松诱导的谷氨酸摄取活性的PHFA。综上所述，我们的数据表明，头孢曲松是一种有效的调节剂谷氨酸转运PHFA通过NF-κ B介导的EAAT 2启动子激活。这些研究结果表明，头孢曲松调节谷氨酸转运的机制，并通过调节细胞外谷氨酸改善特定的神经退行性疾病的潜在影响。
Glutamate is an essential neurotransmitter regulating brain functions. Excitatory amino acid transporter ( EAAT)-2 is one of the major glutamate transporters primarily expressed in astroglial cells. Dysfunction of EAAT2 is implicated in acute and chronic neurological disorders, including stroke/ischemia, temporal lobe epilepsy, amyotrophic lateral sclerosis, Alzheimer disease, human immunodeficiency virus 1-associated dementia, and growth of malignant gliomas. Ceftriaxone, one of the beta-lactam antibiotics, is a stimulator of EAAT2 expression with neuroprotective effects in both in vitro and in vivo models based in part on its ability to inhibit neuronal cell death by glutamate excitotoxicity. Based on this consideration and its lack of toxicity, ceftriaxone has potential to manipulate glutamate transmission and ameliorate neurotoxicity. We investigated the mechanism by which ceftriaxone enhances EAAT2 expression in primary human fetal astrocytes (PHFA). Ceftriaxone elevated EAAT2 transcription in PHFA through the nuclear factor-kappa B (NF-kappa B) signaling pathway. The antibiotic promoted nuclear translocation of p65 and activation of NF-kappa B. The specific NF-kappa B binding site at the -272 position of the EAAT2 promoter was responsible for ceftriaxone-mediated EAAT2 induction. In addition, ceftriaxone increased glutamate uptake, a primary function of EAAT2, and EAAT2 small interference RNA completely inhibited ceftriaxone-induced glutamate uptake activity in PHFA. Taken together, our data indicate that ceftriaxone is a potent modulator of glutamate transport in PHFA through NF-kappa-Bmediated EAAT2 promoter activation. These findings suggest a mechanism for ceftriaxone modulation of glutamate transport and for its potential effects on ameliorating specific neurodegenerative diseases through modulation of extracellular glutamate.