Role of Neuroinflammation in Surgery-Induced Cognitive Impairments

Neuroinflammation has become a hallmark of several neurological disorders and a critical driver of cognitive deficits. The mechanisms underlying postoperative neuroinflammation are complex and yet poorly defined. Using a clinically relevant mouse model of orthopedic surgery, we started to define a key role for surgical trauma in causing neuroinflammation and memory impairments. Pro-inflammatory cytokines, danger-associated molecular patterns, macrophage migration, blood-brain barrier disruption, and neuronal dysfunction have been causally related to POCD in animal models and early clinical studies. Ongoing efforts in the lab are focusing on the mechanisms of neuroinflammation, in particular, the role of microglia after surgery, pain signaling, and how these factors contribute to neuronal dysfunction and behavioral deficits after trauma and during ageing.

Bioelectronic Regulation of Neuroinflammation and Memory Function

Aside from being fundamental organizational units of the nervous system and regulating a myriad of organ functions, neural reflexes are also capable of controlling inflammation. Our previous work revealed that pharmacological activation of a cholinergic anti-inflammatory reflex could mitigate surgery-induced neuroinflammation and POCD in mice. We are currently focusing on the interactions between the nervous and immune systems. Current efforts are aimed at developing novel strategies to activate these signaling pathways and regulate postoperative inflammation with electrical nerve stimulation. Bioelectronic medicine may provide a novel therapeutic approach to prevent POCD by modulating cholinergic function and replacing pharmacological agents with ensuing side effects. This project brings together a multidisciplinary team of investigators from Duke University and is developed in close collaboration with Professor Warren Grill in Duke Biomedical Engineering. It was selected for a 2016 Duke Institute for Brain Sciences (DIBS) Incubator award.

Pro-Resolving Strategies for Postoperative Cognitive Disorders

Resolution of inflammation is an active process where synthesis and release of anti-inflammatory molecules is required for balancing the overall immune response. Our lab first reported on the effects of resolvins, lipid mediators generated by omega-3 essential fatty acids, in preventing neuroinflammation and memory deficits after surgery. Current studies are looking into the mechanisms of actions of these molecules into the brain. Dr. Zhiquan Zhang discovered a bioactive peptide from Annexin-A1, and ongoing efforts are evaluating the neuroprotective properties of this compound on the blood-brain barrier and immune cells trafficking after trauma. This is contributing to a holistic approach aimed at defining the role of endogenous pro-resolving mediators not only on the central nervous system, but also in a broader context of perioperative organ protection, healing and resiliency. In collaboration with Dr. Miles Berger in our department, we are attempting to translate preclinical evidence of neuroinflammation into surgical patients, and understand if these lipid mediators may aid diagnosing of postoperative delirium and cognitive decline in at-risk patients.

1. Zhang MD, Barde S, Yang T, Lei B, Eriksson LI, Bakalkin G, Ernfors P, Mathew JP, Akassoglou K, Harkany T, Hökfelt TGM, Terrando N, Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels, Proc. Natl. Acad. Sci. USA; 113(43)E6686-E6695, 2016
2. Terrando N, Yang T, Wang X, Fang J, Cao M, Andersson U, Harris HE, Ouyang W, Tong J, Systemic HMGB1 neutralization prevents postoperative neurocognitive dysfunction in aged rats, Front Inflamm; 7:441, 2016
3. Hirsch J, Vacas S, Terrando N, Yuan M, Sands L, Kramer JH, Bozic KJ, Maze M, Leung JM, Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery, J Neuroinfl; 13(1):211, 2016
4. Steinberg BE, Sundman E, Terrando N, Eriksson LI, Olofsson PS, The neural control of inflammation: implications for perioperative and critical care, Anesthesiology, 124(5): 1174-89, 2016
5. Qiu L, Zhu C, Bodogan T, Galan MG, Zhang Y, Zhou K, Li T, Xu G, Blomgren K, Eriksson LI, Vutskits L, Terrando N, Acute and long-term effects of brief sevoflurane anesthesia during the early postnatal period in rats, Toxicol Sci, 149: 121-133, 2016
6. Terrando N, Eriksson LI, Eckenhoff RG, Perioperative neurotoxicity in the elderly: summary of the 4th International Workshop, Anesth Analg, 120(3):649-52, 2015
7. Terrando N, Yang T, Ryu JK, Monaco C, Feldmann M, Ma D, Akassoglou K, Maze M, Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice, Mol Med; 20:667-75, 2015
8. Terrando N, Gomez M, Yang T, Carlstrom M, Gustvasson D, Harding R, Lindskog M, Eriksson LI, Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline, FASEB J, 27(9):3564-71, 2013
9. Su X, Feng X, Terrando N, Yan Y, Chawla A, Koch L, Britton S, Matthay MA, Maze M, Dysfunction of inflammation-resolving pathways is associated with exaggerated postoperative cognitive decline in a rat model of metabolic syndrome, Mol Med, 18:1481-90, 2013
10. Terrando N, Eriksson LI, Ryu JK, Yang T, Monaco C, Feldmann M, Fagerlund M, Charo I, Akassoglou K, Maze M, Resolving postoperative neuroinflammation and cognitive decline, Ann Neurol, 70(6):986-95, 2011
11. Terrando N, Monaco C, Ma D, Foxwell BJ, Feldmann M, Maze M, From the cover: Tumor necrosis factor-α (TNF-α) triggers a cytokine cascade yielding postoperative cognitive decline. Proc. Natl. Acad. Sci. USA, 107(47): 20518 – 22, 2010

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