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J. Biol. Chem., Vol. 283, Issue 19, 13116-13123, May 9, 2008

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Mechanism of Ceftriaxone Induction of Excitatory Amino Acid Transporter-2 Expression and Glutamate Uptake in Primary Human Astrocytes^*

Seok-Geun Lee¹, Zhao-Zhong Su¹, Luni Emdad^¶, Pankaj Gupta, Devanand Sarkar², Alejandra Borjabad^||**, David J. Volsky^||**, and Paul B. Fisher, Holds the Thelma Neumeyer Corman Chair in Cancer Research and is a SWCRF Investigator^¶||3

From the Departments of Urology, ^¶Neurosurgery, and ^||Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York 10032, ^**Molecular Virology Division, St. Luke's-Roosevelt Hospital Center, New York, New York 10019, and Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298

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 β-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-B (NF-B) signaling pathway. The antibiotic promoted nuclear translocation of p65 and activation of NF-B. The specific NF-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-B-mediated 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.

Received for publication, September 13, 2007 , and in revised form, March 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant P01 NS31492 (to D. J. V. and P. B. F.). This work was also supported by the Samuel Waxman Cancer Research Foundation (SWCRF) (to P. B. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² The Harrison Endowed Scholar in Cancer Research.

³ To whom correspondence should be addressed: Dept. of Human and Molecular Genetics, VCU Inst. of Molecular Medicine, Massey Cancer Center, 1101 E. Marshall St., Sanger Hall Bldg., Richmond, VA 23298. Fax: 804-827-1124; E-mail: pbfisher{at}vcu.edu.