Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein–induced Inflammation through a Vagomimetic Action in Mice

Abstract

Background Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-associated molecular pattern–induced cognitive decline. Methods Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines. Results Damage-associated molecular pattern–induced cognitive decline and inflammation (mean ± SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 ± 8.69% vs. 41.45 ± 7.64%, P < 0.0001; plasma interleukin [IL]-1β: 7.0 ± 2.2 pg/ml vs. 49.8 ± 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 ± 1.6 pg/ml vs. 19.5 ± 1.7 pg/ml, P < 0.0001; hippocampal IL-1β: 4.1 ± 3.0 pg/mg vs. 41.6 ± 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 ± 1.3 pg/mg vs. 16.2 ± 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation–resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 ± 0.1 vs. 0.7 ± 0.1, P < 0.0001; spleen: 1.5 ± 0.2 vs. 0.6 ± 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 ± 0.2 vs. 0.9 ± 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 ± 0.2 vs. 3.0 ± 0.3, P < 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade. Conclusions Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern–mediated cognitive decline.

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

“…Human PMN swarming activates a temporal biosynthetic code that produces stop signals, e.g., LXA 4 and resolvins, at critical PMN densities (183). Temporal biosynthesis with lipid mediator class switching is documented in hu man blisters (157) and with specific drugs (184) (e.g., dexmedetomidine) that can prevent cognitive decline by activating SPMs (185). In randomized trials, immunonutrition (dietary interventions that modulate the immune system) increases RvE1 in patients undergoing hepatobiliary surgery, giving lower rates of infection complications and severity (186).…”

Dysfunction of the Autonomic Nervous System and Its Role in the Pathogenesis of Septic Critical Illness (Review)

“…In this case, dexmedetomidine prevented the inflammation-induced activation of microglia [68]. This α2-adrenergic agonist regulates gene expression, activation of cell channels, release of transmitters, inflammation, and cellular apoptosis [69][70][71][72][73][74][75].…”

Dexamethasone and dexmedetomidine as adjuvants to local anesthetic mixture in intercostal nerve block for thoracoscopic pneumonectomy: a prospective randomized study

“…Both dexamethasone and dexmedetomidine can reduce local inflammation and prolong the duration of nerve block through vasoconstriction by maintaining the local concentration of the local anesthetic. [11][12][13][14] Vasoconstriction also inhibits the nociceptive impulse transmission along myelinated C fibers. 15 Possible mechanisms of dexmedetomidine in prolonging the duration of nerve blocks may also include the inhibition of the hyperpolarization-activated cation current (Ih current).…”