Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats.

Niccolò Terrando,Wen Ouyang,Jianbin Tong,Ting Yang,Xueqin Wang,Jiakai Fang,Harris Helena Erlandsson,Ulf Andersson,Mengya Cao

doi:10.3389/fimmu.2016.00441

Abstract

Postoperative neurocognitive disorders are common complications in elderly patients following surgery or critical illness. High mobility group box 1 protein (HMGB1) is rapidly released after tissue trauma and critically involved in response to sterile injury. Herein, we assessed the role of HMGB1 after liver surgery in aged rats and explored the therapeutic potential of a neutralizing anti-HMGB1 monoclonal antibody in a clinically relevant model of postoperative neurocognitive disorders. Nineteen to twenty-two months Sprague-Dawley rats were randomly assigned as: (1) control with saline; (2) surgery, a partial hepatolobectomy under sevoflurane anesthesia and analgesia, + immunoglobulin G as control antibody; (3) surgery + anti-HMGB1. A separate cohort of animals was used to detect His-tagged HMGB1 in the brain. Systemic anti-HMGB1 antibody treatment exerted neuroprotective effects preventing postoperative memory deficits and anxiety in aged rats by preventing surgery-induced reduction of phosphorylated cyclic AMP response element-binding protein in the hippocampus. Although no evident changes in the intracellular distribution of HMGB1 in hippocampal cells were noted after surgery, HMGB1 levels were elevated on day 3 in rat plasma samples. Experiments with tagged HMGB1 further revealed a critical role of systemic HMGB1 to enable an access to the brain and causing microglial activation. Overall, these data demonstrate a pivotal role for systemic HMGB1 in mediating postoperative neuroinflammation. This may have direct implications for common postoperative complications like delirium and postoperative cognitive dysfunction.

Highlights

Postoperative neurocognitive disorders, encompassing postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common complications in elderly patients over 65 years of age following surgery or critical illness [1]
Rabbit/monoclonal Synthetic peptide corresponding to Human high mobility group box 1 (HMGB1) aa 150 to the C-terminus Rabbit/monoclonal Synthetic phoshopeptide corresponding to residues surrounding Serine 133 of human CREB Rabbit/polyclonal Synthetic peptide corresponding to C-terminus of Iba1 Rabbit/monoclonal Synthetic peptide corresponding to Human NMDAR2A Rabbit/polyclonal Synthetic peptide conjugated to KLH derived from within residues 1450 to the C-terminus of
Our data indicate a key role for peripherally released HMGB1 causing neuroinflammation and memory dysfunction after abdominal surgery

Summary

INTRODUCTION

Postoperative neurocognitive disorders, encompassing postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common complications in elderly patients over 65 years of age following surgery or critical illness [1]. HMGB1 and Memory surgery [2] Occurrence of these postoperative complications significantly associate with increased morbidity and mortality, greater length of hospital stay, increased costs, and decreased life independence [3]. Damage-associated molecular pattern molecules (DAMPs), in particular high mobility group box 1 (HMGB1), are rapidly released after tissue trauma and mediate immune cell recruitment and activation, cytokine release, and cell death [5]. Anti-HMGB1 mAb treatment increased phosphorylation of cyclic AMP response element binding (p-CREB) in the hippocampus after surgery, suggesting that anti-HMGB1 exerts neuroprotective effects in aged rats. These effects on neuroinflammation and synaptic plasticity may inform on pathophysiological mechanisms of delirium and other postoperative neurocognitive disorders appearing after surgery

MATERIALS AND METHODS

RESULTS

DISCUSSION