P058: PERIOPERATIVE CHOLINERGIC DISRUPTION AND 7 NICOTINIC ANTI-INFLAMMATORY SIGNALING AS A MECHANISTIC LINK BETWEEN ANTICHOLINERGIC BURDEN AND POSTOPERATIVE DELIRIUM
Shrishti Singh1; Brienna Chan1; Nayade Caldes1; Mayur Parmar, PhD1; Yiying Zhang, MD, PhD2; Xie Zhongcong, MD, PhD3
1NOVA Southeastern University Dr. Kiran C Patel College of Osteopathic Medicine; 2Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital and Harvard Medical School; 3Department of Anesthesia, Critical Care and Pain Medicine at The University of Texas Health Science Center at McGovern Medical School
Introduction: Postoperative Delirium (POD) is a common perioperative neurocognitive disorder linked to prolonged recovery. Reduced cholinergic signaling, potentially resulting from advanced age, surgical stress, and perioperative administration of anticholinergic drugs, may contribute to the exacerbation of POD.
Methods: A mechanistic synthetic review was conducted to examine the emerging relationship between reduced cholinergic signaling, neuroinflammation, and vulnerability to POD in perioperative geriatric patients.
Results: Aging is associated with diminished cholinergic tone, reduced acetylcholine release, and decreased receptor sensitivity. Additionally, perioperative anesthetic agents such as isoflurane and propofol reduce acetylcholine reserves. Collectively, these factors disrupt cholinergic homeostasis and are associated with increased circulating proinflammatory cytokines (IL-1β, IL-6, TNF-α).
Cholinergic disruption promotes microglial activation, astrocyte dysfunction, and compromised blood-brain barrier (BBB) integrity. Anticholinergic agents such as atropine and scopolamine suppress muscarinic receptor signaling, which increases the circulation of inflammatory cytokines like IL-1β. Scopolamine has also been shown to specifically activate the NLRP3 inflammasome, which further increases cytokine production. Collectively, intact muscarinic cholinergic signaling is neuroprotective by limiting cytokine- and microglial-driven neuroinflammation and preserving cognitive function.
In parallel, decreased activity of the α7 nicotinic acetylcholine receptor (α7nAChR) elevates cytokines IL-1β, IL-6, and TNF-α, exacerbating the pro-inflammatory pathway. Loss of α7nAChR-mediated regulation results in enhanced activation of NF-κB, JAK2-STAT3, PI3K/AKT, and MAPK signaling cascades, amplifying pro-inflammatory cytokine release.
This feed-forward inflammatory cycle, alongside muscarinic receptor inhibition, exacerbates microglial activation and further impairs BBB integrity. Disruption of both nicotinic and muscarinic receptors can have a synergistic effect, contributing to worsened cognitive dysfunction.
The disruption of the blood-brain barrier resulting from the inflammatory cytokine release into the brain parenchyma can lead to neurocognitive disorders. The neuroinflammatory cascade seen in these mechanisms increases the risk of POD.
Conclusion: Perioperative cholinergic imbalance driven by aging, surgical stress, anesthetic exposure, and atropinic burden may represent a mechanistic link between systemic inflammation and postoperative delirium. Emerging evidence suggests that activation of α7nAChR has been further shown to improve cognitive deficits and amnesia caused by scopolamine in primate and rodent models, suggesting a more protective role against cholinergic disruptions. Targeting cholinergic signaling pathways, particularly the modulation of α7nAChR-mediated anti-inflammatory mechanisms and the neuroprotective functions of muscarinic receptors, may present a promising intervention for reducing POD risk in vulnerable older adults. Future therapeutic models can focus on reducing the cumulative cholinergic imbalance in perioperative geriatric patients.
Figure: Proposed Mechanistic Model of Perioperative Cholinergic Disruption and Cognitive Vulnerability
