Abstract
Inflammation and neonatal hypoxia-ischemia (HI) are important etiological factors of perinatal brain injury. However, underlying mechanisms remain unclear. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases. Sirtuin-6 is thought to regulate inflammatory and oxidative pathways, such as the extracellular release of the alarmin high mobility group box-1 (HMGB1). The expression and role of sirtuin-6 in neonatal brain injury are unknown. In a well-established model of neonatal brain injury, which encompasses inflammation (lipopolysaccharide, LPS) and hypoxia-ischemia (LPS+HI), we investigated the protein expression of sirtuin-6 and HMGB1, as well as thiol oxidation. Furthermore, we assessed the effect of the antioxidant N-acetyl cysteine (NAC) on sirtuin-6 expression, nuclear to cytoplasmic translocation, and release of HMGB1 in the brain and blood thiol oxidation after LPS+HI. We demonstrate reduced expression of sirtuin-6 and increased release of HMGB1 in injured hippocampus after LPS+HI. NAC treatment restored sirtuin-6 protein levels, which was associated with reduced extracellular HMGB1 release and reduced thiol oxidation in the blood. The study suggests that early reduction in sirtuin-6 is associated with HMGB1 release, which may contribute to neonatal brain injury, and that antioxidant treatment is beneficial for the alleviation of these injurious mechanisms.
Highlights
The complex etiology underlying perinatal brain injury includes, among other factors, inflammation and neonatal hypoxiaischemia (HI) (Hagberg et al, 2015)
Sirtuin 6 has been suggested as a regulator of high mobility group box-1 (HMGB1) release
We found that the area of extracellular HMGB1 staining in the ipsilateral hippocampus was significantly smaller in the N-acetyl cysteine (NAC) group compared with the VEH group (Figure 5C, n = 6–8/group, p = 0.041)
Summary
The complex etiology underlying perinatal brain injury includes, among other factors, inflammation and neonatal hypoxiaischemia (HI) (Hagberg et al, 2015). Inflammation, acting in combination with neonatal HI, increases the risk of perinatal brain injury, as shown in both rodents (Eklind et al, 2001, 2005; Wang et al, 2009) and larger animals (Martinello et al, 2019). Sirtuins are located in different subcellular compartments (Houtkooper et al, 2012). Melatonin-mediated protection against LPS-induced neuronal damage in the dentate gyrus of rats was shown to involve upregulation of SIRT1 and the antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which caused a reduction in inflammation and oxidative stress (Shah et al, 2017)
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