Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats

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.

Endotoxin tolerance induced by lipopolysaccharide preconditioning protects against surgery‑induced cognitive impairment in aging mice

“…These data confirm previous findings demonstrating the role of neuroinflammation in the development of POCD (11). For example, inhibition of IL-1 receptors, or prophylactic treatment of mice with either a monoclonal antibody to TNF-α or by disabling HMGB1 with an inhibitory monoclonal antibody, may improve post-surgical cognitive decline (10)(11)(12)18). Although specific neutralization of the pro-inflammatory mediators appears promising in animal studies, anti-cytokine drugs are not selective to particular tissues and frequently produce undesirable side effects in clinical practice.…”

“…Thus, from a clinical perspective, suppressing inflammation represents a legitimate way to reduce surgery-induced cognitive impairment. In support of this hypothesis, it has been reported that prophylactic administration of either a Endotoxin tolerance induced by lipopolysaccharide preconditioning protects against surgery-induced cognitive impairment in aging mice monoclonal antibody to TNF-α, or disabling HMGB1 with an inhibitory monoclonal antibody, improves post-surgical cognitive decline (10)(11)(12). However, direct neutralization of these pro-inflammatory mediators may lead to undesirable side effects.…”

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

“…HMGB1, a ubiquitously expressed molecule, has been shown to increase in the circulation in rats with aging (Fonken et al ., 2016; Terrando et al ., 2016) and to increase RANKL expression in osteocytic cells (Yang et al ., 2008). However, we did not find changes in HMGB1 levels in the serum of old mice (Fig.…”

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

“…HMGB1 stimulated leukocyte chemotaxis and activation ex vivo [158–160] and induced microglial activation, increased neuroinflammation, and exacerbated neurocognitive deficits, at least in part, via a TLR-dependent mechanism in several non-traumatic injury models [161–163]. The passive release of HMGB1 from NMDA-injured neurons similarly increased pro-inflammatory activation in primary human and murine microglia via a TLR4-dependent mechanism [73, 164].…”