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.