In amyotrophic lateral sclerosis, down-regulation of the astrocyte-specific 
glutamate excitatory amino acid transporter 2 is hypothesized to increase 
extracellular glutamate, thereby leading to excitotoxic motor neuron death. The 
antibiotic ceftriaxone was recently reported to induce excitatory amino acid 
transporter 2 and to prolong the survival of mutant superoxide dismutase 1 
transgenic mice. Here we show that ceftriaxone also protects fibroblasts and the 
hippocampal cell line HT22, which are not sensitive to excitotoxicity, against 
oxidative glutamate toxicity, where extracellular glutamate blocks cystine 
import via the glutamate/cystine-antiporter system x(c)(-). Lack of 
intracellular cystine leads to glutathione depletion and cell death because of 
oxidative stress. Ceftriaxone increased system x(c)(-) and glutathione levels 
independently of its effect on excitatory amino acid transporters by induction 
of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), 
a known inducer of system x(c)(-), and the specific x(c)(-) subunit xCT. No 
significant effect was apparent in fibroblasts deficient in Nrf2 or xCT. Similar 
ceftriaxone-stimulated changes in Nrf2, system x(c)(-), and glutathione were 
observed in rat cortical and spinal astrocytes. In addition, ceftriaxone induced 
xCT mRNA expression in stem cell-derived human motor neurons. We conclude that 
ceftriaxone-mediated neuroprotection might relate more strongly to activation of 
the antioxidant defense system including Nrf2 and system x(c)(-) than to 
excitatory amino acid transporter induction.