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Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro
Author(s) -
Lewerenz Jan,
Albrecht Philipp,
Tien MaiLy Tran,
Henke Nadine,
Karumbayaram Saravanan,
Kornblum Harley I.,
WiedauPazos Martina,
Schubert Dave,
Maher Pamela,
Methner Axel
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06347.x
Subject(s) - neuroprotection , excitotoxicity , glutamate receptor , glutathione , ceftriaxone , oxidative stress , superoxide dismutase , biology , pharmacology , biochemistry , extracellular , chemistry , microbiology and biotechnology , antibiotics , receptor , enzyme
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.