Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro

Abstract

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 xc−. Lack of intracellular cystine leads to glutathione depletion and cell death because of oxidative stress. Ceftriaxone increased system xc− 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 xc−, and the specific xc− subunit xCT. No significant effect was apparent in fibroblasts deficient in Nrf2 or xCT. Similar ceftriaxone‐stimulated changes in Nrf2, system xc−, 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 xc− than to excitatory amino acid transporter induction.

Targeting Astrocytes for Stroke Therapy

“…However, because CFX induces the expression of the transcription factors NF-B and Nrf2, CFX may protect against cell death through multiple mechanisms. 66,67 In contrast to its administration before stroke, administration of CFX 30 minutes after the onset of ischemia did not significantly reduce stroke volume. 65 This lack of protection is not surprising, given that glutamate excitotoxicity is such an early event after onset of ischemia.…”

Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

“…Moreover, ATF4 contributes to the induction of xCT mRNA transcription in response to amino acid deprivation or proteasome inhibition, in the latter case together with Nrf2 (34, 57). Electrophiles and oxidative stress in general also up-regulate xCT expression in an Nrf2-dependent manner in various cells, including cancer and neural cells (13,35,36). In these cases, Nrf2 regulation likely occurs via an antioxidant/electrophile response element in the Slc7a11 gene (35).…”

“…In this regard, the 5Ј-flanking region of the murine xCT gene contains multiple putative transcription factor binding sites that contribute to the stimulus and/or cell type-dependent regulation of xCT gene transcription (3,7,13,(33)(34)(35)(36). In addition to transcriptional regulation, the mRNA of xCT contains a long 3Ј-UTR, ϳ7366 nucleotides, raising the possibility for post-transcriptional regulation as well.…”

Astrocytic transporters in Alzheimer's disease

“…To date, however, there are no studies characterising changes in CT, 4F2hc levels or xc-activity in AD or animal models of AD disease. Nonetheless, neuroprotective properties of ceftriaxone in an animal model of motor neuron disease have been attributed to its ability to induce XCT (190) but, paradoxically, deletion of XCT reduces symptoms in a transgenic mouse model of motor neuron disease (191). Therefore, it remains to be demonstrated if system xc-is a worthwhile target in the search for novel AD therapeutics.…”