Class IIa HDAC Downregulation Contributes to Surgery-Induced Cognitive Impairment Through HMGB1-Mediated Inflammatory Response in the Hippocampi of Aged Mice

Abstract

Objective Perioperative neurocognitive disorders (PND) are a common complication in the elderly. Histone deacetylases (HDACs) are a class of enzymes that control the acetylation status of intracellular proteins. Thus, we explored whether HDACs trigger the release of high mobility group box 1 (HMGB1) through altering the acetylation status in the hippocampi of aged mice. Materials and Methods The effect of the Class IIa HDAC in PND was explored using an in vivo form of splenectomy. Sixteen-month-old healthy male C57BL/6J mice were randomly divided into five groups: control, anesthesia plus sham surgery, anesthesia plus splenectomy, LMK235 treatment, and PBS treatment. The hippocampi were harvested on either first, third, or seventh postoperative day. Cognitive function was assessed via a Morris water maze (MWM) test. Quantitative RT-PCR, Western blots and ELISAs were carried out to assess the targeted gene expression at transcriptional and translational levels. Results Splenectomy led to a significant deficiency in spatial memory acquisition, marked decreases in mRNA and protein levels of HDAC4 and HDAC5 in the hippocampus, and increases in the levels of total HMGB1 and acetylated HMGB1. In a similar fashion to splenectomy, treatment with the HDAC4/5 inhibitor LMK235 produced impaired spatial memory and an increase in the expression of HMGB1 and its acetylated counterpart in the hippocampus. Conclusion These results suggest that surgery leads to PND through class IIa HDAC downregulation-triggered HMGB1 release in hippocampus of aged mice. HDACs may be a potential therapeutic target for postoperative cognitive dysfunction.

SIRT1 Downregulation Contributes to Surgery-Induced Cognitive Impairment Through Autophagy-Mediated NLRP3 Inflammasome Activation in the Hippocampi of Aged Mice

“…Splenectomy was performed as previously described [13]. Brie y, mice were induced into a mixture of 8% sevo urane and 100% oxygen and subsequently maintained with 2% sevo urane and 100% oxygen for the duration of the surgery.…”

Overexpression of SESN1 improves mitochondrial damage and mitophagy, a potential therapeutic strategy for cognitive dysfunction after anaesthesia

“…Conversely, autophagy enhancement appears beneficial for animal learning and memory, capable of inhibiting NLRP3 inflammasome formation and alleviating cognitive impairment (Ye et al, 2019; Zheng et al, 2023; Zhou et al, 2023). The sirtuin family, particularly SIRT1, has been demonstrated to prevent energy metabolism and ageing via diacylation, playing pivotal roles in processes including apoptosis, autophagy, development, metabolism and circadian rhythm regulation (Fang et al, 2020). SIRT1 downregulation was found to induce cognitive impairment via autophagy inhibition and apoptosis activation, while SIRT1, which negatively regulates the NLRP3 inflammasome, could suppress inflammatory responses (Hu et al, 2020).…”

Trilobatin rescues cognitive impairment of Alzheimer’s disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway

“…Of note, translocation of HMGB1 from the nucleus to cytosol is affected by post-translational modifications, including acetylation, which are mediated through the equilibrium of histone deacetylases (HDACs) and histone acetyltransferases. Sirtuins are an evolutionarily conserved family of nicotinamide adenine dinucleotide-dependent lysine deacylase, and also classified as class III HDACs due to their capacity to eliminate acetyl from lysine residues on histones proteins [13]. Among the SIRT family (SIRT1-7), SIRT3 is a primary mitochondrial lysine deacetylase with the highest deacetylase activity, and regulates mitochondrial function, reactive oxygen species (ROS) levels and neuroinflammation [14].…”