Activation of Nrf2-Regulated Glutathione Pathway Genes by Ischemic Preconditioning

Abstract

Prophylactic pharmacological activation of astrocytic gene expression driven by the transcription factor Nrf2 boosts antioxidant defences and protects against neuronal loss in ischemia and other disease models. However, the role of Nrf2 in mediating endogenous neuroprotective responses is less clear. We recently showed that Nrf2 is activated by mild oxidative stress in both rodent and human astrocytes. Moreover, brief exposure to ischemic conditions was found to activate Nrf2 both in vivo and in vitro, and this was found to contribute to neuroprotective ischemic preconditioning. Here we show that transient ischemic conditions in vitro and in vivo cause an increase in the expression of Nrf2 target genes associated with the glutathione pathway, including those involved in glutathione biosynthesis and cystine uptake. Taken together, these studies indicate that astrocytic Nrf2 may represent an important mediator of endogenous neuroprotective preconditioning pathways.

Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury

“…As ethical considerations do not allow for the use of brief repeated occlusion of the cerebral arteries to elicit stroke tolerance in humans, animal models of chemical preconditioning have been actively investigated in hopes to develop a clinically-useful approach to stroke preconditioning in humans. Moreover, chemical preconditioning may also be useful as a prophylactic approach to neuroprotection [11, 12]. The reason for this is that while the onset of stroke is often sudden and unpredictable, individuals with a higher than normal risk of stroke could benefit from prior measures that enhance the brain’s tolerance to potential ischemic injury.…”

Effects of cefazolin and cefoperazone on glutamate transporter 1 isoforms and cystine/glutamate exchanger as well as alcohol drinking behavior in male alcohol-preferring rats

“…Importantly, depletion in glutathione content is associated with decreased xCT expression (Bell et al, 2011; Lewerenz et al, 2009). Ceftriaxone treatment was shown neuroprotection by inducing nuclear factor-erythroid 2-related factor (Nrf2)-mediated induction of xCT expression, leading to increase in intercellular glutathione levels (Bell et al, 2011; Lewerenz et al, 2009). A critical role of xCT has also been demonstrated in animal models of drug addiction.…”

Redox Signaling Pathways Involved in Neuronal Ischemic Preconditioning

“…The group Bell et al, demonstrated that pure neuronal cultures were unable to upregulate antioxidant genes under Nrf2-transcriptional control, suggesting that astrocytes are the primary source of Nrf2 production and activation. Finally, homozygous Nrf2 knockout mice were not protected from induction of IPC or exposure hydrogen peroxide following OGD, supporting the contributive role of Nrf2 to mediating IPC-induced neuroprotection [171].…”