The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment

Abstract

Postoperative cognitive dysfunction (POCD) is a common complication of the surgical experience and is common in the elderly and patients with preexisting neurocognitive disorders. Animal and human studies suggest that neuroinflammation from either surgery or anesthesia is a major contributor to the development of POCD. Moreover, a large and growing body of literature has focused on identifying potential risk factors for the development of POCD, as well as identifying candidate treatments based on the neuroinflammatory hypothesis. However, variability in animal models and clinical cohorts makes it difficult to interpret the results of such studies, and represents a barrier for the development of treatment options for POCD. Here, we present a broad topical review of the literature supporting the role of neuroinflammation in POCD. We provide an overview of the cellular and molecular mechanisms underlying the pathogenesis of POCD from pre-clinical and human studies. We offer a brief discussion of the ongoing debate on the root cause of POCD. We conclude with a list of current and hypothesized treatments for POCD, with a focus on recent and current human randomized clinical trials.

Keywords: anesthesia; central nervous system; cognitive decline; microglia; neuroinflammation; postoperative cognitive dysfunction.

Figure 1

Signaling pathways involved in peripheral initiation of inflammation. Injured cells release damage-associated molecular patterns (DAMPs) including high mobility group box-1 protein (HMGB1) in response to surgical trauma. HMGB1 activates nuclear factor-kappa B (NF-κB) signaling pathways in bone marrow derived monocytes (BMDMs), causing nuclear translocation of NF-κB, increased expression of cyclooxygenase 2 isozyme (COX-2) upregulation, and expression of pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFα). These pro-inflammatory cytokines can act back on BMDMs in positive feedback loops (solid curved lines) as well as promote further release of HMGB1 from injured cells by unknown mechanisms (dashed curved lines). IKK, IκB kinase; IL-6R, IL-6 receptor; P, phosphate group; RAGE, receptor for advanced glycosylation end products; TLR-4, Toll-like receptor 4; TNFαR, TNFα receptor.

Figure 2

Signaling pathways involved in blood-brain barrier (BBB) breakdown. Pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα) are secreted by bone marrow derived monocytes (BMDMs) and cause upregulation of nuclear factor-kappa B (NF-κB) and matrix metalloproteinase (MMP) expression in vascular endothelial cells. NF-κB activation causes downstream upregulation of cyclooxygenase 2 isozyme (COX-2) expression, which promotes prostaglandin synthesis and disrupts BBB permeability. Once the BBB is disrupted, BMDMs can enter the central nervous system (CNS); here, the pro-inflammatory cytokines IL-1 and TNFα promote the activation of quiescent microglia. These microglia promote further release of IL-1 and TNFα from BMDMs, as well as secrete high mobility group box-1 protein (HMGB1) and the chemokine monocyte chemo-attractant protein 1 (MCP-1, also called C-C motif ligand 2 (CCL2)). MCP-1/CCL2 binds to the BMDM cell surface receptor chemokine receptor type 2 (CCR2), further promoting BMDM migration into the CNS. AA, arachidonic acid; PGE2, prostaglandin E2; PGH2, prostaglandin H2; TLR-4, Toll-like receptor 4.

Figure 3

Cholinergic anti-inflammatory pathway. (A) schema of vagal reflex arc. Damage-associated molecular patterns (DAMPs) are sensed by vagal afferents; the efferent vagal arc terminates in the celiac ganglion onto splenic nerve fibers, ultimately causing downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines. (B) cellular signaling within the cholinergic anti-inflammatory pathway. Splenic nerve endings terminate near T lymphocytes and increase acetylcholine (ACh) production via β₂ adrenergic receptors (β₂-ARs). The expressed ACh can activate circulating macrophages via alpha-7 nicotinic ACh receptors (α7 nAChRs). Activation of α7 nAChRs causes downstream inhibition of NF-kB activation, ultimately decreasing pro-inflammatory cytokine release. CNX, cranial nerve X (vagus nerve); DMN, dorsal motor nucleus of the vagus; IL, interleukin; NE, norepinephrine; NTS, nucleus tractus solitarius; P, phosphate group; TLR-4, Toll-like receptor 4; TNFα, tumor necrosis factor alpha.