Surgery, neuroinflammation and cognitive impairment

Azeem Alam, Zac Hana, Zhaosheng Jin, Ka Chun Suen, Daqing Ma, Azeem Alam, Zac Hana, Zhaosheng Jin, Ka Chun Suen, Daqing Ma

Abstract

Trauma experienced during surgery can contribute to the development of a systemic inflammatory response that can cause multi-organ dysfunction or even failure. Post-surgical neuroinflammation is a documented phenomenon that results in synaptic impairment, neuronal dysfunction and death, and impaired neurogenesis. Various pro-inflammatory cytokines, such as TNFα, maintain a state of chronic neuroinflammation, manifesting as post-operative cognitive dysfunction and post-operative delirium. Furthermore, elderly patients with post-operative cognitive dysfunction or delirium are three times more likely to experience permanent cognitive impairment or dementia. We conducted a narrative review, considering evidence extracted from various databases including Pubmed, MEDLINE and EMBASE, as well as journals and book reference lists. We found that further pre-clinical and well-powered clinical studies are required to delineate the precise pathogenesis of post-operative delirium and cognitive dysfunction. Despite the burden of post-operative neurological sequelae, clinical studies investigating therapeutic agents, such as dexmedetomidine, ibuprofen and statins, have yielded conflicting results. In addition, evidence supporting novel therapeutic avenues, such as nicotinic and HMGB-1 targeting and remote ischaemic pre-conditioning, is limited and necessitates further investigation.

Keywords: Inflammation; Multiple organ dysfunction syndrome; Neuroinflammation; Surgery; Systemic inflammatory response syndrome; Therapeutic targets.

Copyright © 2018. Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
End organ effects of postoperative systemic inflammatory response syndrome (SIRS). Surgical dissection and its associated trauma cause cell death which, in turn, results in the release of intracellular components into the extracellular space. These include immunogenic compounds such as RNA and DAMPs (HMGB-1, ATP and Histone) which bind to and activate specific toll-like receptors (TLRs), driving the NFκB mediated transcription of pro-inflammatory cytokines. Furthermore, activated T cells release pro-inflammatory mediators and can cause direct cytotoxicity. These processes result in tissue injury, oedema and inflammation and ultimately damage organs. ALI, acute lung injury. ARDS, acute respiratory distress syndrome. BBB, blood brain barrier. GFR, glomerular filtration rate. SVR, systemic vascular resistance.
Fig. 2
Fig. 2
Mechanism of post-operative neuroinflammation. DAMPs and PAMPs activate the downstream pathway involved in inducing the production of TNFα, as well as other proinflammatory mediators via NF-κB. This causes the loss of blood-brain barrier (BBB) integrity, due to endothelial dysfunction occurs and increased permeability of the BBB. As a result, there is a recruitment of circulating lymphocytes into the neuronal tissue, and microglia and astrocytes are activated. Cytokines induce the synthesis and release of NO via inducible nitric oxide synthase from the activated microglia and astrocytes. Also, cytokines cause an increase in intracellular Ca2+. In addition, GSK-3 dysfunction occurs in neuroinflammation, which potentiates microglial activation and migration and stimulates cells to produce NO and TNFα via NF-κB activation. Subsequently, neuroinflammation leads to neuronal apoptosis, reduced hippocampal neurogenesis, impaired synaptic plasticity and a loss of synaptic connections. All of this, in turn, leads to neurodegenerative conditions such as post-operative cognitive dysfunction and increased risk of Alzheimer's disease. BBB, blood brain barrier. DAMP, danger associated molecular pattern. GSK-3, Glycogen synthase kinase-3. iNOS, inducible nitric oxide synthase. NO, nitric oxide. TLR, toll like receptor.

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Source: PubMed

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