title: Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics.
abstract: Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Analysis of the 2.5  kb human EAAT2 promoter showed that NF-κB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many β-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a β-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes through the NF-κB signaling pathway. The NF-κB binding site at -272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298, USA. kkim5@vcu.edu
authors.forename: Keetae
authors.initials: K
authors.lastname: Kim
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kegelman
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Paola M
authors.initials: PM
authors.lastname: Barral
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Paul
authors.initials: P
authors.lastname: Diaz
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D018698:Glutamic Acid