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