Time-Dependent Effects of Systemic Lipopolysaccharide Injection on Regulators of Antioxidant Defence Nrf2 and PGC-1α in the Neonatal Rat Brain

Abstract

Background/Aims: Both excitotoxicity and neuroinflammation are associated with oxidative stress. One transcription factor, nuclear factor E2-related factor 2 (Nrf2), and one transcription cofactor, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), increase the endogenous antioxidant defence and can thus modulate neuronal cell death. Here, we investigated the temporal effects (after 24 and 72 h) of systemic (i.p.) administration of lipopolysaccharide (LPS) on the cerebral Nrf2 and PGC-1α systems. Methods and Results: Seven-day-old rat pups were injected with LPS (0.3 mg/kg). After 24 h, the protein levels of γ-glutamylcysteine ligase modulatory subunit, γ-glutamylcysteine ligase catalytic subunit, Nrf2, PGC-1α and manganese superoxide dismutase (MnSOD) were increased in parallel with decreased levels of Keap1. These effects were correlated with an increased level of phosphorylated Akt and elevated acetylation of histone 4. In contrast, 72 h following LPS, a decrease in the components of the Nrf2 system in parallel with an increase in Keap1 was observed. The down-regulation after 72 h correlated with phosphorylation of p38 mitogen-activated protein kinase, while there were no changes in PGC-1α and MnSOD protein levels or the acetylation/methylation pattern of histones. Conclusion: Systemic LPS in neonatal rats induced time-dependent changes in brain Nrf2 and PGC-1α that correlated well with the protective effect observed after 24 h (pre-conditioning) and the deleterious effects observed after 72 h (sensitizing) of systemic LPS reported earlier. Collectively, the results point towards Nrf2 and PGC-1α as a possible mechanism behind these effects.

NRF2-regulation in brain health and disease: Implication of cerebral inflammation

“…There are few previous reports on such a link, but a recent study suggests that GSK3-β can directly phosphorylate and activate one HDAC subtype, which then exerts neurotoxic effects (89). Similar, but less pronounced, effects on the NRF2 system in brains were observed in vivo in LPS injected 8 day old rats (90). …”

“…(A) Based on our studies (45, 85, 86, 90) we suggest that acute inflammation can oxidize/modify certain thiols in the KEAP1 dimer and activate kinases such as AKT, ERK and JNK. This will lead to that NRF2 escapes from being ubiquinated by Cullin-3 (Cul3) and then transported to the nucleus, a process that is promoted by phosphorylation.…”

“…overactivation of microglia and elevated levels of proinflammatory cytokines, leads to sustained activation of GSK-3β and p38 (45, 85, 86, 90). We propose that the activation of GSK-3β and p38 leads to phosphorylation of NRF2 at sites that enhance the binding to KEAP1, which will elevate the ubiquitination of NRF2 and thereby enhance degradation.…”

Dichloroacetate treatment improves mitochondrial metabolism and reduces brain injury in neonatal mice

“…DCA treatment increased mitochondrial biogenesis-related Pgc-1α mRNA at 6 h and Nrf-1 mRNA at 24 h after HI, but not Tfam mRNA. The different expression profiles of these genes might be related to different temporal changes after HI [32, 33]. Even though one of the mitochondria-specific proteins increased at 24 h after HI with DCA treatment, there was no change in mtDNA copy number in the normal controls at either 6 h or 24 h after HI.…”

Sustained Effects of Neonatal Systemic Lipopolysaccharide on IL-1β and Nrf2 in Adult Rat Substantia Nigra Are Partly Normalized by a <b><i>Spirulina</i></b>-Enriched Diet

“…We have shown earlier in in vitro and in vivo studies that inflammation by LPS can cause a down-regulation in the Nrf2-system up to 3 days after treatment [13–15]. Here we used a model where LPS is injected i.p.…”