Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro.
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.
Lewerenz
Jan
J
Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Albrecht
Philipp
P
Tien
Mai-Ly Tran
ML
Henke
Nadine
N
Karumbayaram
Saravanan
S
Kornblum
Harley I
HI
Wiedau-Pazos
Martina
M
Schubert
Dave
D
Maher
Pamela
P
Methner
Axel
A
D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D026922:Amino Acid Transport Systems, Acidic; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002443:Ceftriaxone / Q000494:pharmacology*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D013116:Spinal Cord / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D027182:Amino Acid Transport System y+; D026922:Amino Acid Transport Systems, Acidic; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D018698:Glutamic Acid; D005978:Glutathione; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; C118895:SLC7A11 protein, human; C000606290:SOD1 protein, human; C492255:Slc7a11 protein, mouse; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; C000723960:Slc7a11 protein, rat