N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice

Gagandeep Singh-Mallah; Takuya Kawamura; Maryam Ardalan; Tetyana Chumak; Pernilla Svedin; Peter G Arthur; Christopher James; Henrik Hagberg; Mats Sandberg; Carina Mallard

doi:10.3389/fncel.2021.743093

N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice

Front Cell Neurosci. 2021 Nov 15:15:743093. doi: 10.3389/fncel.2021.743093. eCollection 2021.

Authors

Affiliations

¹ Centre of Perinatal Medicine and Health, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
² Department of Obstetrics and Gynecology, Mie University, Tsu, Japan.
³ School of Molecular Sciences, University of Western Australia, Perth, WA, Australia.
⁴ Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵ Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

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.

Keywords: high-mobility group box 1 protein; hypoxia-ischemia; lipopolysaccharide; n-acetyl cysteine; sirtuins.