Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats.

Area of Science:

• Neuroscience
• Immunology
• Gerontology

Background:

• Postoperative neurocognitive disorders are frequent in elderly patients after surgery or critical illness.
• High mobility group box 1 protein (HMGB1) is released after tissue trauma and implicated in sterile injury responses.
• HMGB1's role in surgery-induced neuroinflammation and cognitive decline, particularly in aged populations, requires further elucidation.

Purpose of the Study:

• To investigate the role of HMGB1 in the development of postoperative neurocognitive disorders in aged rats following liver surgery.
• To evaluate the therapeutic potential of a neutralizing anti-HMGB1 monoclonal antibody in a preclinical model of postoperative neurocognitive disorders.

Main Methods:

• A partial hepatolobectomy was performed on aged Sprague-Dawley rats under sevoflurane anesthesia.
• Animals were treated with either saline, control immunoglobulin G, or an anti-HMGB1 monoclonal antibody.
• Neurocognitive function, hippocampal phosphorylated cyclic AMP response element-binding protein levels, plasma HMGB1, and microglial activation were assessed.

Main Results:

• Systemic anti-HMGB1 antibody treatment prevented surgery-induced memory deficits and anxiety in aged rats.
• This neuroprotection was associated with the prevention of reduced hippocampal phosphorylated cyclic AMP response element-binding protein.
• Elevated plasma HMGB1 levels were observed on day 3 post-surgery, and systemic HMGB1 was found to facilitate brain entry and microglial activation.

Conclusions:

• Systemic HMGB1 plays a critical role in mediating postoperative neuroinflammation and cognitive dysfunction in aged rats.
• Targeting HMGB1 with monoclonal antibodies represents a promising therapeutic strategy for preventing postoperative neurocognitive disorders, including delirium and cognitive dysfunction.