Neuroimmune synapse and modulation by anesthetics: Inflammatory mechanisms and therapeutic perspectives for postoperative neurocognitive disorders

Abstract

Postoperative delirium and postoperative cognitive dysfunction are common complications after anesthesia and surgery, particularly in older adults, and they substantially impair recovery quality and long-term outcomes. Neuroinflammation is widely recognized as a central mechanism, yet its origins and regulatory hubs remain incompletely defined. This review introduces the emerging concept of the “neuroimmune synapse (NIS)” as a critical interface that links immune regulation within the central nervous system to neuronal function, and it advances a new perspective on its role in anesthesia and surgery related neuroinflammation and cognitive impairment. We delineate the structural basis of the NIS, which is primarily constituted by microglia, astrocytes, and neurons. We summarize key signaling pathways, including the CX3C chemokine ligand 1/CX3CR1 and CD200/CD200R axes, the complement cascade, and the triggering receptor expressed on myeloid cells 2/DNAX activation protein of 12 kDa complex, and we outline their core physiological roles in maintaining synaptic homeostasis and immune surveillance. We then focus on the potential direct and indirect effects of different classes of anesthetics, including inhalational agents, propofol, benzodiazepines, ketamine, dexmedetomidine, and opioids, on the structure and function of the NIS, and analyze how these agents may disrupt neuroimmune dialogue. We propose that anesthesia and surgery act as combined stressors that perturb NIS function, for example by inducing aberrant microglial activation, promoting excessive release of proinflammatory mediators, and driving over-pruning of synapses. These processes can initiate and sustain neuroinflammatory cascades in the brain, leading to synaptic dysfunction and loss in key regions such as the hippocampus and prefrontal cortex, which represents a core pathological link to postoperative delirium and cognitive impairment. A NIS centered framework provides a new explanation for the vulnerability of high-risk populations, particularly older adults, and highlights potential avenues for intervention through optimized anesthetic strategies, such as agent selection and multimodal analgesia, or through targeting pivotal synaptic immune mediators, including CX3CR1, triggering receptor expressed on myeloid cells 2, and complement components. This review aims to catalyze research across disciplines and to establish a conceptual basis for innovative approaches to prevent and treat postoperative neurocognitive complications.

Key Words: Postoperative neurocognitive disorders; Neuroimmune synapse; Microglia-neuron interactions; Neuroinflammation; Anesthetic modulation; Complement system; Synaptic pruning

Core Tip: This review reinterprets postoperative neurocognitive disorders through the concept of the neuroimmune synapse (NIS), the microglia, astrocyte, and neuron interface coordinating immune and neuronal signaling. We synthesize evidence on NIS pathways (CX3C chemokine ligand 1/CX3CR1, CD200/CD200R, complement, triggering receptor expressed on myeloid cells 2/DNAX activation protein of 12 kDa), show how anesthesia combined with surgical stress perturbs NIS function, and link aberrant microglial activation, excessive synaptic pruning, and hippocampal and prefrontal dysfunction to postoperative neurocognitive disorders. We further outline how distinct anesthetic classes modulate NIS structure and signaling, and propose testable interventions: Agent selection, multimodal analgesia, and targeting CX3CR1, triggering receptor expressed on myeloid cells 2, and complement to restore synaptic homeostasis.

INTRODUCTION

Postoperative neurocognitive disorders (PND), which encompass postoperative delirium (POD), postoperative cognitive dysfunction (POCD), and delayed neurocognitive recovery, are common perioperative neurological complications, with a particularly high incidence among older adults. While PND refers to a spectrum of cognitive disturbances that occur following surgery, POCD specifically focuses on the long-term cognitive decline observed after surgery, typically seen in older adults. It is important to note that while PND and POCD share overlapping mechanisms, they are not identical conditions. However, for the purpose of understanding the underlying biological mechanisms, studies using POCD mouse models are often referenced, as these models closely mimic the neuroinflammatory processes and cognitive dysfunction observed in PND[1-4]. PND not only prolongs hospitalization and increases healthcare costs but is also closely associated with reduced quality of life, long-term cognitive decline, and higher mortality[1,5]. With rapid population aging and rising surgical volumes worldwide, prevention and management of PND have become major clinical challenges at the intersection of anesthesiology, geriatrics, and neuroscience[6,7].

Although the pathophysiology of PND is multifactorial and complex, growing evidence converges on neuroinflammation as a central hypothesis[3,8-10]. Surgical injury, anesthetic exposure, and other perioperative stressors can initiate inflammatory cascades in the peripheral and central nervous systems (CNS), disrupt neuronal homeostasis, and ultimately impair cognition[11,12]. A pivotal process involves intricate inflammatory crosstalk between the peripheral immune system and the brain’s innate immune network. Within this context, the concept of the neuroimmune synapse (NIS) offers a fresh framework for understanding disease mechanisms. The NIS refers to direct interactions between immune cells and neurons, as well as the broader set of molecules and signaling pathways that mediate their communication.

As the resident immune cells of the CNS, microglia and astrocytes provide the cellular foundation of neuroinflammation through their activation states, dysfunction, and intercellular interactions[2,9]. In parallel, breakdown of blood-brain barrier (BBB) integrity, gut microbiota dysbiosis with aberrant gut-brain axis signaling, and circulating inflammatory mediators together form conduits that transmit inflammatory information from the periphery to the CNS[1,13,14]. This review aims to systematize the neuroinflammation-centered pathophysiology of PND, with in-depth discussion of the roles of glial cells, mitochondrial biology, synaptic plasticity, and epigenetic regulation. We further analyze how different anesthetics and perioperative interventions exert dual modulatory effects on neuroinflammation, and we outline emerging prevention and treatment strategies grounded in these mechanisms to inform clinical practice and translational research.

CENTRAL MECHANISM OF PND: THE NEUROINFLAMMATION HYPOTHESIS

The neuroinflammation hypothesis posits that dysregulated or excessive inflammatory responses triggered by perioperative factors, including surgical trauma and anesthetic exposure, are the key drivers of PND onset and progression[3,10]. The process is initiated in the periphery. Surgical injury causes tissue damage and releases large quantities of damage-associated molecular patterns (DAMPs), such as high mobility group box 1 (HMGB1), mitochondrial DNA (mtDNA), and S100 proteins[13]. These DAMPs activate peripheral immune cells and induce abundant production of proinflammatory cytokines, which culminates in a cytokine storm. Peripheral inflammatory signals then reach the CNS through multiple routes, disrupt the state of relative immune privilege, and initiate neuroinflammation[8,9] (Figure 1). At the core of neuroinflammation is the activation and functional dysregulation of resident innate immune cells in the CNS, namely microglia and astrocytes. Under physiological conditions they maintain central homeostasis. Under pathological stimulation they shift toward a proinflammatory phenotype and release cytokines, chemokines, and reactive oxygen species, which directly or indirectly injure neurons, impair synaptic structure and function, and ultimately manifest as cognitive deficits[2]. This hypothesis conceptualizes PND as a central projection of a systemic inflammatory response and emphasizes complex immune communication between the periphery and the brain, thereby providing an integrative framework for understanding the pathophysiology of PND.

Figure 1 Schematic illustration of the neuroinflammatory mechanisms underlying the pathogenesis of postoperative neurocognitive disorders. Perioperative factors such as surgery and anesthesia activate the peripheral immune system, triggering the release of damage-associated molecular patterns and a subsequent cytokine surge. These inflammatory signals reach the central nervous system through multiple routes, including disruption of the blood-brain barrier and dysregulation of the gut-brain axis, ultimately resulting in neuronal injury. Within the central nervous system, microglia become activated and polarize toward a pro-inflammatory M1 phenotype, releasing inflammatory mediators and undergoing pyroptosis. Key regulatory molecules such as triggering receptor expressed on myeloid cells 2, CD33, and P2X7 receptor, which modulate microglial activity, display abnormal expression and further amplify neuroinflammation. At the same time, astrocytic dysfunction occurs. This includes reduced expression of the glucose transporter 1 transporter on the cell membrane and abnormal expression of neurotransmitter-regulating transporters such as glutamate transporter 1. These changes disrupt energy metabolism and impair neurotransmitter homeostasis. In addition, harmful interactions between microglia and astrocytes continually intensify the neuroinflammatory cascade. Other mechanisms, including blood-brain barrier impairment, disturbances of the gut-brain axis, extracellular vesicle trafficking, and excessive release of pro-inflammatory cytokines, also contribute to the pathogenesis of postoperative neurocognitive disorders. Together, these processes lead to synaptic dysfunction and neuronal injury, which ultimately result in cognitive decline and the clinical onset of postoperative neurocognitive disorders. PND: Postoperative neurocognitive disorders; M1: Pro-inflammatory microglial phenotype; M2: Anti-inflammatory microglial phenotype; TREM2: Triggering receptor expressed on myeloid cells 2; P2X7R: P2X7 receptor; TNF-α: Tumor necrosis factor-α; IL: Interleukin; GLUT1: Glucose transporter 1; GLT-1: Glutamate transporter 1; A1: Neurotoxic reactive astrocyte phenotype; BBB: Blood-brain barrier; EVs: Extracellular vesicles; DAMPs: Damage-associated molecular patterns.

Microglia as master regulators of neuroinflammation

As the resident immune cells of the CNS, microglia serve as principal regulators in the neuroinflammatory pathology of PND[2]. In physiological states they are surveillant and highly ramified. Through continuous monitoring of the microenvironment with fine processes they support synaptic pruning and remodeling and they modulate neural circuits[15]. When challenged by surgical trauma, anesthetic agents, or peripheral inflammatory signals, microglia become rapidly activated and undergo marked morphological and functional changes. They transition from guardians of homeostasis to dominant effectors of inflammatory responses[8,9,16].

Activation, polarization, and phenotypic switching: Microglial activation is a dynamic process that involves polarization toward distinct functional phenotypes. The traditional framework divides activated microglia into a proinflammatory M1 phenotype and an antiinflammatory M2 phenotype. In PND models, microglia show marked polarization toward M1, characterized by robust release of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), together with reactive oxygen species, which aggravate neuronal injury and synaptic dysfunction[17,18] (Figure 1). Long noncoding RNA AC020978 can intensify PND by promoting glycolysis and M1 polarization through regulation of pyruvate kinase M2[17]. In contrast, several therapeutic approaches aim to reprogram microglia toward the M2 phenotype with enhanced phagocytosis, tissue repair, and antiinflammatory activity. For example, the endogenous myokine irisin induces M2 transition via signal transducer and activator of transcription 6 signaling and prevents postoperative cognitive deficits[19]. Caffeic acid phenethyl ester acts through the sirtuin (SIRT) 6 and nuclear factor erythroid-2-related factor 2 axis[20], resveratrol acts through the SIRT1 and nuclear factor-κB (NF-κB) axis[21], and chitinase-3-like protein 1 promotes M2 polarization via extracellular signal-regulated kinase signaling[22], all conferring neuroprotection. Anesthetics themselves can bidirectionally modulate microglial activation. Proinflammatory or antiinflammatory effects depend on the agent used, its dose and exposure duration, and the host condition, underscoring the complexity of phenotype regulation[23].

Pyroptosis as an inflammatory cell death program: Pyroptosis is a form of programmed cell death mediated by inflammatory caspases and defined by membrane pore formation and cytosolic content release that elicits vigorous inflammation. Microglial pyroptosis has emerged as an important mechanism of neuroinflammation in PND[24] (Figure 1). Surgical stress and anesthetic exposure can activate multiple inflammasomes in microglia, with the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome being particularly prominent[25,26]. NLRP3 functions as a key innate immune sensor that detects exogenous pathogens and endogenous cellular injury[15]. Upon sensing danger signals, activated NLRP3 assembles the inflammasome and promotes conversion of procaspase-1 to active caspase-1. Active caspase-1 processes the precursors of IL-1β and IL-18 into their mature forms and facilitates their release, which amplifies inflammation. Caspase-1 also cleaves gasdermin D to generate an N-terminal fragment that forms membrane pores and causes pyroptotic cell death[25,27]. In PND models, blocking microglial pyroptotic pathways mitigates neuroinflammation and cognitive impairment. Histone lactylation suppresses sevoflurane-induced microglial pyroptosis through the YTH domain family member 3 (YTHDF3) and peroxiredoxin-3 axis[24]. Inhibiting histone deacetylase 6 (HDAC6) limits pyroptosis by modulating interactions of heat shock protein (HSP) 90 and HSP70 with NLRP3[25]. Propofol can induce pyroptosis in juvenile rats via the NLRP3 and caspase-1 pathway, whereas pathway inhibition reverses this neurotoxicity[27]. These findings identify microglial pyroptosis as a promising therapeutic target for PND.

Key regulatory molecules, triggering receptor expressed on myeloid cells 2, CD33, and P2X7 receptor: Microglial functional states are finely tuned by surface receptors and associated molecules, several of which play pivotal roles in PND. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly enriched in microglia and shows context dependent actions. Activation of TREM2 can restrain neuroinflammation through the phosphoinositide 3-kinases and protein kinase B (AKT) pathway and improve POCD[28]. In a model of sevoflurane induced developmental neurotoxicity, however, TREM2 overexpression protected synapses by enhancing microglial pruning of dendritic spines, indicating condition specific functions[29]. CD33 is another major immunoregulatory receptor whose upregulation correlates with cognitive impairment. Surgery and anesthesia can increase CD33 expression. Inhibition of CD33 attenuates neuroinflammation and cognitive deficits through a TREM2 dependent mechanism, suggesting that CD33 may promote neuroinflammation by suppressing TREM2 function[30]. The purinergic receptor P2X7 receptor (P2X7R) is an ATP gated ion channel with a prominent role in inflammatory signaling. After surgery, hippocampal expression of P2X7R and its downstream effector caspase-1 increases. Pharmacologic inhibition or genetic deletion of P2X7R reduces neuroinflammation and cognitive deficits[31] (Figure 1). P2X4 receptor involvement in POCD has also been reported, and its antagonists confer cognitive benefit[32]. These molecules provide precise targets for therapeutic modulation of microglial function.

Role of CD200/CD200R and CX3C chemokine ligand 1/CX3CR1 axes: The activation regulation of microglia is closely associated with the development of PND. The CD200/CD200R and CX3C chemokine ligand 1 (CX3CL1)/CX3CR1 axes are two key inhibitory signaling pathways that play a central role in regulating the activation state of microglia. The CD200/CD200R axis transmits inhibitory signals from neuronal CD200 to microglia, limiting their overactivation. However, surgical stress, inflammation, or aging can downregulate CD200 or impair CD200R signaling, weakening this immune control and leading to amplified pro-inflammatory responses, synaptic damage, and increased cognitive vulnerability, all of which are closely associated with the development of PND[33]. Studies have shown that restoring CD200-CD200R interactions significantly reduces inflammatory cytokine release and improves cognitive function[34].

CX3CL1, a chemokine secreted by neurons, interacts with its receptor CX3CR1 on microglia, regulating their activation. Under normal conditions, the CX3CL1/CX3CR1 axis prevents excessive microglial activation and maintains CNS immune homeostasis[35]. However, surgical injury, systemic inflammation, or aging can disrupt this regulatory mechanism, leading to microglial overactivation and neuroinflammation, which contribute to PND. Research has shown that restoring CX3CL1/CX3CR1 signaling helps reduce microglial activation, suppress neuroinflammation, and improve postoperative cognitive function[36,37]. Together, these findings suggest that both the CD200/CD200R and CX3CL1/CX3CR1 axes may serve as potential therapeutic targets for PND, particularly in the regulation of microglial function.

Astrocytes as key co-operators in neuroinflammation

Astrocytes are the most abundant glial cells in the CNS. They are indispensable for neuronal function, synaptic homeostasis, and energy metabolism[38]. In the pathophysiology of PND, astrocytes are not passive bystanders. They act as essential co-operators that participate in and amplify neuroinflammatory injury through multiple pathways[9].

Energy metabolism and neuronal support, exemplified by glucose transporter 1: Astrocytes take up glucose from the circulation through glucose transporter 1 on the cell surface and convert it into energy substrates such as lactate. Through the astrocyte to neuron lactate shuttle, they provide metabolic support to neurons[39]. In aged mouse models of POCD, hippocampal astrocytic glucose transporter 1 expression is markedly reduced. The resulting energy shortfall compromises the structural and functional plasticity of dendritic spines and culminates in cognitive impairment (Figure 1). Targeted overexpression of glucose transporter 1 in hippocampal astrocytes using viral vectors alleviates these deficits and improves learning and memory[39]. These findings reveal the importance of astrocyte mediated metabolic dysregulation in PND and suggest that improving brain energy supply is a potential therapeutic strategy.

Dysregulation of neurotransmitter homeostasis: Astrocytes clear synaptic neurotransmitters through glutamate transporters such as glutamate transporter 1 (GLT-1) and through γ-aminobutyric acid (GABA) transporters. In this way they maintain the balance between excitation and inhibition and protect neurons from overexcitation and excitotoxicity[40]. Type 2 diabetes, a risk factor for PND, reduces GLT-1 expression in hippocampal astrocytes of adult mice. Although GLT-1 downregulation alone does not necessarily cause cognitive decline, surgical anesthesia on top of this vulnerability markedly enhances glutamatergic overexcitation, triggers oxidative stress and neuronal apoptosis, and leads to POCD[41] (Figure 1). Under inflammatory stimulation, reactive astrocytes aberrantly synthesize and release GABA through a process mediated by monoamine oxidase B. In aged mouse PND models, GABA levels are abnormally elevated in reactive astrocytes. Inhibition of monoamine oxidase B with selegiline reduces GABA production and improves cognition[42]. These observations indicate that astrocytic failure to regulate neurotransmitter homeostasis is a critical component of PND pathology.

Crosstalk between astrocytes and microglia: Astrocytes and microglia engage in close communication and mutual regulation that shape the neuroinflammatory milieu. In PND models, early activated microglia release mediators such as IL-1α, TNF-α, and C1q, which drive astrocytes toward the neurotoxic A1 phenotype[43]. A1 astrocytes lose supportive functions and actively release toxic factors that induce rapid death of neurons and oligodendrocytes. Single-cell sequencing further shows that reactive microglia aggravate astrocytic cytotoxicity through the complement pathway and related mechanisms in the postoperative aged hippocampus[44]. Conversely, astrocytes modulate microglial states by releasing cytokines and neurotrophic factors and by signaling through gap junctions such as connexin 43[45,46]. After surgery, astrocytes may secrete the chemokine C-C motif ligand 2, also known as monocyte chemoattractant protein-1. Binding of C-C motif ligand 2 to CC chemokine receptor 2 on microglia triggers microglial activation and shifts their phenotype toward M1, increases production of proinflammatory cytokines including TNF-α and IL-1β, amplifies neuroinflammation, and promotes neuronal apoptosis[47] (Figure 1). Extracellular vesicles represent another important route of intercellular communication. Astrocyte derived exosomes can deliver protective microRNA 26a-5p to neurons and, by regulating the AKT, glycogen synthase kinase-3 beta, and collapsin response mediator protein 2 pathway, attenuate sevoflurane induced neuronal apoptosis and dendritic abnormalities, thereby improving cognition[48]. This intricate bidirectional network highlights the value of treating glia as an integrated system when designing interventions.

Peripheral-central inflammatory crosstalk: Pathways constituting the neuroimmune interaction

The core pathology of PND is neuroinflammation within the CNS. The initiating forces, however, often arise from peripheral surgical injury and systemic inflammatory responses[3,13]. In the narrow sense, the NIS refers to the direct signaling interface between immune cells (such as microglia and T cells) and neurons, mediating bidirectional communication between electrical activity and immune signaling[49]. However, under pathological conditions such as PND, where systemic inflammation affects brain function, peripheral inflammatory signals engage in dynamic information exchange with the CNS through multiple indirect pathways. Therefore, in this study, we adopt a broader concept of the “neuroimmune synapse” to describe the interactive mechanisms by which peripheral inflammatory signals communicate with the central immune system via the BBB, the gut-brain axis, and circulating mediators. Although these pathways do not form classical synaptic structures, they collectively constitute a functional communication network between the immune and nervous systems, representing a key component in the pathogenesis of PND.

Disruption and increased permeability of the BBB, exemplified by matrix metalloproteinase-9 and DAMPs

The BBB is a structural and functional cornerstone of central homeostasis (Figure 1). During surgical stress, peripheral damage associated molecular patterns such as HMGB1 and proinflammatory cytokines including IL-1β and TNF-α act on endothelial cells, pericytes, and astrocytic endfeet, which leads to barrier dysfunction[13,50]. Matrix metalloproteinase 9 is a key effector. Anesthesia and surgery upregulate matrix metalloproteinase-9 (MMP 9) in the context of peripheral inflammation. MMP 9 degrades tight junction proteins such as zonula occludens-1 and claudin 5 and also disrupts components of the basal lamina, thereby compromising barrier integrity[51,52]. Increased permeability permits infiltration of peripheral inflammatory cells such as neutrophils and monocytes and diffusion of cytokines and DAMPs into the CNS. These signals directly activate microglia and astrocytes, amplify neuroinflammatory cascades, impair synaptic function, and promote neuronal apoptosis, which ultimately damages cognition[14,52]. Inhibition of MMP 9[51] or neutralization of HMGB1[53] can preserve barrier integrity, attenuate neuroinflammation, and improve postoperative cognition. Interventions such as electroacupuncture have also been reported to lower barrier permeability through suppression of MMP 9, providing neuroprotection[54].

The gut brain axis, impacts of dysbiosis and microbial metabolites: The gut brain axis provides bidirectional communication between the intestinal microbiota and the CNS and has received growing attention in PND[1,6] (Figure 1). Perioperative stress, anesthetics, and antibiotics can induce dysbiosis and disrupt the intestinal barrier, which leads to a leaky gut[55]. Dysbiosis allows translocation of harmful bacteria and products such as lipopolysaccharide into the circulation and triggers systemic inflammation. In parallel, production of beneficial metabolites declines, notably short chain fatty acids such as butyrate[56]. Butyrate exerts antiinflammatory and neuroprotective effects, supports BBB integrity, and directly modulates microglial function. Sevoflurane exposure in neonatal mice induces microbial imbalance and lowers short chain fatty acids, which impairs oligodendrocyte differentiation and myelination. Butyrate supplementation reverses these abnormalities[56]. Clinical and preclinical studies indicate that perioperative probiotics can reshape the microbiome, reduce inflammatory mediators such as IL-1β and IL-6, and lower the incidence of PND[57,58]. Probiotics can also mitigate cardiopulmonary bypass related brain injury and cognitive deficits by modulating the kynurenine pathway[59]. These observations underscore the importance of preserving gut homeostasis for PND prevention and provide a rationale for emerging strategies such as fecal microbiota transplantation.

Circulating inflammatory mediators, cytokines and extracellular vesicles: The circulation constitutes the most direct route for peripheral to central inflammatory crosstalk. Following surgical trauma, peripheral immune cells and injured tissues release large amounts of cytokines, including IL-1β, IL-6 and TNF-α[60-62] (Figure 1). These mediators can act on the BBB and can also signal to the brain through afferent pathways such as the vagus nerve[63]. Clinically, elevated postoperative plasma IL-6 and its soluble receptor correlate with the risk of POD, which suggests an important role for IL-6 trans signaling[61]. Plasma IL-6 levels are closely related to one-year cognitive recovery and long-term impairment after major surgery in older adults[59]. Age strongly conditions barrier disruption and cognitive deficits induced by anesthesia and surgery, and systemic deletion of IL-6 markedly alleviates these postoperative injuries[64]. Beyond soluble cytokines, extracellular vesicles, particularly exosomes, are emerging carriers of intercellular communication in PND[65]. Extracellular vesicles encapsulate proteins and microRNAs, traverse the BBB, and deliver peripheral pathological information to central targets such as neurons and microglia[66]. Transferring circulating extracellular vesicles collected from anesthetized and operated mice into healthy recipients induces delirium like behaviors and neuronal pathology. These pathogenic vesicles are enriched in serum amyloid A1 as well as microRNAs such as miR-103-3p and miR-31-5p, which likely serve as key messengers that relay peripheral injury to the brain[66]. These insights deepen our mechanistic understanding of inflammatory crosstalk and point to extracellular vesicles as promising diagnostic biomarkers and therapeutic carriers for PND. The BBB, gut-brain axis, and circulating inflammatory mediators are key routes through which peripheral inflammation affects the CNS. While not classical NIS, these pathways extend the concept of neuro-immune communication and underscore the multi-level role of a “broad” NIS in PND.

Aging and neuroinflammation

Aging is widely recognized as one of the most important independent risk factors for PND[67]. The aging brain is more vulnerable to PND due to several key changes in the neuroimmune system. As individuals age, the NIS undergoes significant alterations that impair its function, leading to dysregulated neuroinflammatory responses following surgical stress[68]. One of the key changes in the aging brain is the phenomenon of “inflammaging”, characterized by a chronic low-grade inflammatory state that primes microglia and other immune cells for an exaggerated response to injury or infection. This age-associated inflammation contributes to a heightened neuroinflammatory response in the elderly brain, exacerbating the effects of surgical trauma and increasing the susceptibility to PND[69]. Additionally, microglial senescence, characterized by reduced phagocytic activity and altered cytokine production, contributes to the dysfunction of the NIS, further amplifying neuroinflammation after surgery[70]. These changes make the aged brain more prone to cognitive dysfunction following surgical insults, underlining the critical role of age in PND pathophysiology.

CELLULAR AND MOLECULAR MECHANISMS UNDERPINNING PND

Within the overarching context of neuroinflammation, the evolution of PND involves intertwined cellular and molecular pathologies. These alterations form a continuum from macroscopic stressors to microscopic injury and culminate in cognitive impairment. In the previous section, we offered a preliminary understanding of the neuroinflammation hypothesis. In this section, we will examine the pathogenesis of PND in greater detail, focusing on microscopic injury. Key mechanisms, including mitochondrial dysfunction, synaptic plasticity impairments, and dysregulated epigenetic processes, have been intensively studied and represent crucial links in this progression.

Mitochondrial dysfunction: Cellular energy crisis and oxidative stress

Neurons are highly energy demanding cells whose function depends on mitochondrial ATP production. Perioperative stressors, including surgery and anesthetic exposure, can directly or indirectly impair mitochondrial function and trigger an energy crisis and oxidative stress. This constitutes an early and central event in PND pathogenesis[71]. Hallmarks include respiratory chain inhibition, reduced ATP generation, loss of mitochondrial membrane potential, abnormal calcium buffering, and iron accumulation[71,72]. A defining feature of PND models is disruption of mitochondrial integrity. Mitofusin 2, a core mediator of endoplasmic reticulum to mitochondria coupling, is essential for organelle homeostasis. Loss of mitofusin 2 causes excessive endoplasmic reticulum and mitochondria contacts, mitochondrial calcium overload, and apoptosis[73]. Repeated sevoflurane exposure in neonatal mice downregulates hippocampal mitofusin 2, disrupts mitochondria associated membranes, and impairs mitochondrial function. Overexpression of mitofusin 2 reverses neuron loss and cognitive deficits. Repeated ketamine anesthesia also reduces mitofusin 2 in hippocampal neural stem cells and eventually leads to impaired synaptic plasticity and long-term cognitive problems[74,75].

Mitophagy and quality control, exemplified by PTEN-induced putative kinase 1: Mitophagy is the principal quality control pathway that removes damaged mitochondria and preserves a healthy mitochondrial network. The PTEN induced kinase 1 and Parkin pathway plays a central role[76]. In PND models, mitophagy is compromised, which allows dysfunctional mitochondria to accumulate in microglia and neurons[77]. Damaged mitochondria release mtDNA into the cytosol and activate the cyclic GMP-AMP (cGAS) stimulator of interferon genes (STING) pathway, a key innate immune signaling axis that further promotes NLRP3 inflammasome activation and type I interferon responses, thereby intensifying neuroinflammation[77,78] (Figure 2). Enhancing mitophagy is therefore an attractive strategy. Pharmacologic activation with agents such as the PTEN-induced putative kinase 1 agonist tamarixetin reduces cytosolic mtDNA and reactive oxygen species, suppresses neuroinflammation, and improves cognition in surgical models[76]. Maintaining a normal flux of mitophagy is critical for restraining the inflammatory surge associated with PND.

Figure 2 Three core pathological links of postoperative neurocognitive disorders: Mitochondrial dysfunction, impaired synaptic plasticity and abnormal epigenetic regulation. (1) Mitochondrial dysfunction: Impaired mitophagy leads to the accumulation of dysfunctional mitochondria. Leakage of mitochondrial DNA activates the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 inflammasome, while dysregulation of antioxidant pathways, reduced ATP production, disrupted endoplasmic reticulum-mitochondria contacts, and excessive mitochondrial fission collectively promote neuronal apoptosis; (2) Impairment of synaptic plasticity: Imbalances in excitatory and inhibitory neurotransmission, loss of dendritic spines, neuronal death, and related mechanisms ultimately damage synaptic structure and function; and (3) Abnormal epigenetic regulation: The circular RNA circITSN1 modulates inflammatory signaling by sequestering eukaryotic initiation factor 4A-III, whereas histone lactylation regulates nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 inflammasome activation through the YTH domain family member 3/peroxiredoxin-3 axis. These epigenetic mechanisms contribute to the long-term pathophysiological changes of postoperative neurocognitive disorders. Together, these three interconnected levels form a cascade of damage that extends from subcellular organelles to neural network function, constituting the molecular basis of cognitive impairment in postoperative neurocognitive disorders. MtDNA: Mitochondrial DNA; NLRP3: Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; Nrf2: Nuclear factor erythroid 2 related factor 2; SIRT3: Sirtuin 3; ROS: Reactive oxygen species; Mito: Mitochondria; ER: Endoplasmic reticulum; MFN2: Mitofusin 2; Drp1: Dynamin-related protein 1; GABA: γ-aminobutyric acid; NO: Nitric oxide; TNF-α: Tumor necrosis factor-α; Ach: Acetylcholine; JNK: C-Jun N-terminal kinase; YTHDF3: YTH domain family member 3; PRDX3: Peroxiredoxin-3.

Oxidative stress and antioxidant pathways, including nuclear factor erythroid 2 related factor 2 and SIRT3: Mitochondria are the primary source of reactive oxygen species. When mitochondria are impaired, excessive reactive oxygen species overwhelm endogenous antioxidant defenses and drive oxidative stress[71]. Oxidative stress damages proteins, lipids, and DNA, which directly compromises neuronal function and viability. Nuclear factor erythroid 2 related factor 2 (Nrf2) is the master transcription factor that coordinates antioxidant and antiinflammatory gene programs[79]. In PND models, Nrf2 signaling is suppressed (Figure 2). Pharmacologic activation with itaconate derivatives such as 4-octyl itaconate or with caffeic acid phenethyl ester, as well as electroacupuncture preconditioning, restores Nrf2 activity, reduces oxidative stress and neuroinflammation in the hippocampus, and ameliorates cognitive deficits[20,80,81]. SIRT3 is the major mitochondrial deacetylase that preserves mitochondrial function and redox balance. SIRT3 deacetylates and activates antioxidant enzymes such as superoxide dismutase 2[82]. After surgery or anesthesia, hippocampal SIRT3 expression declines (Figure 2). Augmenting SIRT3 with small molecules such as magnolol or with viral overexpression enhances antioxidant capacity, restrains neuroinflammation, and protects cognition[82,83]. Strengthening endogenous antioxidant defenses is therefore an effective approach to counter PND related injury.

Mitochondrial dynamics and disturbed energy metabolism: Mitochondrial dynamics, defined by the balance between fission and fusion, are essential for sustaining function and adapting to changing energy demands. This balance is disrupted in PND and related models and is characterized by excessive fission with insufficient fusion[71] (Figure 2). Dynamin related protein 1 mediates fission. Upon phosphorylation, dynamin related protein 1 translocates to the outer mitochondrial membrane and drives fragmentation. Surgical stress inhibits the cold inducible RNA binding protein and thioredoxin 1 pathway and thereby perturbs the subcellular distribution of dynamin related protein 1[84]. Sevoflurane exposure promotes phosphorylation of dynamin related protein 1, exacerbates fission, and worsens cognition in Alzheimer model mice[85]. Proinflammatory mediators such as TNF-α also activate dynamin related protein 1 and induce mitochondrial breakage[72]. Disturbed dynamics directly impair energy metabolism. In Alzheimer models, sevoflurane induced mitochondrial damage shifts cellular metabolism from oxidative phosphorylation toward glycolysis and lowers energetic efficiency[85]. Dysfunction of the calcium transfer complex at mitochondria associated membranes, which comprises inositol 1,4,5 trisphosphate receptor, glucose-regulated protein 75, and voltage-dependent anion channel 1, causes calcium overload and further mitochondrial failure. Intranasal insulin modulates this complex, stabilizes mitochondria associated membranes, and enhances ATP generation, which alleviates PND like phenotypes[86]. Recent work shows that surgery-induced neuroinflammation triggers mitochondrial fission in microglia, promotes cytosolic release of mtDNA, activates the cGAS-STING pathway, thereby aggravating postoperative cognitive impairment[78]. Preserving mitochondrial dynamics and metabolic homeostasis is thus central to neuronal protection.

Impaired synaptic plasticity and neuronal injury

Synapses are the fundamental units for information transmission and storage in the nervous system. Structural and functional plasticity of synapses provides the cellular basis for learning and memory. In PND, a defining pathological outcome is severe disruption of synaptic plasticity. This disruption reflects upstream neuroinflammation and metabolic dysregulation and directly contributes to cognitive impairment[87].

Imbalance of excitatory and inhibitory synapses and receptor dysfunction, including N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid: Learning and memory require a precise balance between excitatory and inhibitory synaptic transmission. This balance is profoundly disturbed in PND models. Glutamatergic neurons release excitatory transmitters into the synaptic cleft to generate excitatory postsynaptic currents. Anesthesia and surgery associated neurocognitive disturbances correlate with reduced excitability of hippocampal glutamatergic neurons and impaired synaptic plasticity[88-90] (Figure 2). Sevoflurane can activate a circuit from the medial prefrontal cortex to the amygdala and produce pathological overexcitation mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in the amygdala, which drives downstream abnormalities[91]. Single nucleus sequencing further shows downregulation of genes related to glutamatergic synapses and reduced synaptic density in hippocampal excitatory neurons of aged mice after sevoflurane exposure[92]. The inhibitory GABA system is also dysregulated (Figure 2). As mentioned in section 2, reactive astrocytes abnormally synthesize and release GABA in response to inflammatory stimuli. Moreover, postoperative hippocampal GABA levels decline, while extrasynaptic GABAA receptors containing the α5 subunit become aberrantly upregulated and enhance persistent tonic inhibition. These changes may reflect long lasting effects of agents such as etomidate and sevoflurane and can be mediated by p38 mitogen-activated protein kinases signaling[93,94]. In addition, transient postoperative neuroinflammation induces sustained downregulation of N-methyl-D-aspartate receptor subunits NR2A and NR2B in the hippocampus and impairs receptor function[95]. Together, these disturbances in the excitatory to inhibitory balance compromise information processing across neural circuits.

Dendritic spine loss and defective structural remodeling

Dendritic spines are the principal sites of excitatory synapses. Dynamic changes in spine density and morphology underlie structural plasticity. A consistent finding in PND models is marked loss of hippocampal dendritic spines with morphological abnormalities[39,87]. Multiple mechanisms contribute to this process. Activated microglia can excessively prune or engulf synapses (Figure 2). In the neonatal sevoflurane exposure model, activation of TREM2 protects against PND by enhancing microglial clearance of dendritic spines. However, in other PND models, excessive microglial phagocytosis of synapses mediated by the complement system (e.g., C1q) leads to synaptic loss and cognitive impairment[29,96]. Post translational modification of tubulin also plays a role (Figure 2). Repeated sevoflurane exposure mislocalizes tau, increases tubulin-tyrosine-ligase-like-6 mediated tubulin polyglutamylation, and elevates the microtubule severing protein spastin, which together impair spine remodeling and promote spine loss[97].

Neuronal apoptosis and pyroptosis: Sustained neuroinflammation and oxidative stress ultimately precipitate neuronal death. Neuronal death is one of the core pathological features in PND, including apoptosis and pyroptosis. Apoptosis is a common form of neuronal loss in PND[98]. Multiple proapoptotic pathways are engaged during postoperative neuroinflammation. Activation of TNF receptor 1 promotes neuronal death, and elevated TNF-α correlates with increased hippocampal apoptosis. Nitric oxide released from activated microglia and astrocytes amplifies inflammation and induces apoptosis. Postoperative activation of mast cells can drive microglial activation through mitogen-activated protein kinases signaling and can also directly contribute to neuronal apoptosis[99,100]. Surgery or anesthesia upregulates proapoptotic proteins such as B-cell lymphoma 2-associated X protein and downregulates antiapoptotic proteins such as B-cell lymphoma 2, which activates caspase 3 and leads to programmed neuronal death[101,102]. Peripheral surgery can also reduce brain acetylcholine content, trigger complex neuroinflammatory responses, and promote degeneration of cholinergic neurons. Cholinergic signaling mediates postoperative secretion of proinflammatory markers such as IL-1β, and decreased acetylcholine elevates multiple proinflammatory cytokines. Inhibition of acetylcholinesterase increases acetylcholine, confers sustained antiinflammatory effects, and provides a potential therapeutic direction for postoperative neuroinflammation[103-105].

Beyond apoptosis, neuronal pyroptosis has received growing attention. While microglial pyroptosis and its association with PND have been discussed, neuronal pyroptosis also contributes to disease progression. Celastrol suppresses the cGAS-STING pathway, reduces cleavage of caspase 3 and gasdermin E, inhibits neuronal pyroptosis, and confers neuroprotection[106]. Neuronal loss in regions that support cognition, notably the hippocampus and prefrontal cortex, marks a transition from functional to structural damage and may lead to persistent or even irreversible cognitive deficits.

Epigenetic and posttranscriptional regulatory mechanisms

Epigenetic regulation modifies gene expression without altering the DNA sequence through DNA methylation, histone modifications, and noncoding RNAs. These mechanisms offer a framework to explain the persistence and susceptibility of PND and function as molecular switches through which environmental factors such as surgery and anesthesia interact with genetic background to produce long lasting pathophysiological changes[107].

Regulatory networks of noncoding RNAs, including circular RNAs and microRNAs: Noncoding RNAs, particularly circular RNAs and microRNAs, form intricate regulatory networks in PND. Circular RNAs are highly stable because of their covalently closed structure and are attractive biomarker candidates. Plasma hsa_circRNA_061570, whose murine ortholog is circITSN1, is markedly upregulated after surgery and correlates with cognitive decline. Mechanistically, neuronal circITSN1 acts as a sponge for the RNA binding protein eukaryotic initiation factor 4A-III, stabilizes Itsn1 mRNA, activates the c-Jun N-terminal kinase inflammatory pathway, and thereby promotes neuroinflammation[108]. MicroRNAs are short noncoding RNAs that repress translation or promote degradation of target mRNAs. Their actions in PND span multiple levels. Astrocytes can deliver protective miR-26a-5p to neurons via exosomes[48]. In contrast, let-7b enhances neuroinflammation through Toll-like receptor (TLR) 7 signaling[109]. MiR-146a exerts antiinflammatory and cognition sparing effects by targeting interleukin-1 receptor associated kinase 1 and TNF receptor-associated factor 6 to inhibit the nuclear factor (NF)-κB pathway[110]. In vitro and in vivo studies show that miR-181b-5p suppresses surgery induced neuroinflammation and lipopolysaccharide triggered microglial activation by inhibiting transcription of TNF-α. Stereotaxic delivery of a miR-181b-5p agonist into the hippocampus reduces neuroinflammation and improves cognition in PND mice[111]. Collectively, these findings identify noncoding RNAs as key regulatory nodes and promising therapeutic targets in the PND cascade.

Roles of histone modifications, exemplified by lactylation: Histone modifications regulate chromatin architecture and transcription. Beyond classical acetylation and methylation, histone lactylation, including H3K18 La, has emerged as a distinctive epigenetic mark in PND[107]. Lactylation links cellular metabolism to transcription by using lactate as a donor. Sevoflurane anesthesia decreases histone lactylation and YTHDF3 expression in the neonatal hippocampus and is accompanied by intensified microglial pyroptosis and inflammation. Further work shows that histone lactylation upregulates YTHDF3, which controls m6A modification and translation of peroxiredoxin-3. This sequence limits NLRP3 inflammasome activation and pyroptosis. Supplementation with lactate or experimental elevation of histone lactylation restores YTHDF3 expression and mitigates sevoflurane induced cognitive deficits[24]. These results reveal a metabolism to epigenetics to immunity axis in PND and suggest that metabolic interventions may improve cognition. Dysregulation of histone deacetylases is also implicated. Overexpression of HDAC6 promotes NLRP3 activation by modulating interactions of HSP90 and HSP70, whereas HDAC6 inhibition confers neuroprotection[25,112].

DUAL REGULATORY EFFECTS OF ANESTHETICS AND PERIOPERATIVE INTERVENTIONS

Anesthetics are indispensable during the perioperative period, yet their impact on the CNS extends well beyond suppression of consciousness and nociception. A growing body of evidence indicates that anesthetics function as a double edged sword. Through direct actions on neurons and glia or indirect modulation of systemic inflammation and stress responses, they exert complex bidirectional influences on the pathogenesis of PND[11,23]. In parallel, perioperative analgesic strategies shape postoperative cognition by regulating inflammatory tone and stress reactivity.

Inhalational anesthetics such as sevoflurane: Construction of PND animal models and potential injury mechanisms

Inhalational anesthetics, particularly sevoflurane and isoflurane, are widely used in clinical practice because of rapid onset and ease of titration. They are also the most common tools for constructing PND animal models[56,58,85,97,113]. Extensive preclinical work has revealed potential neurotoxicity, especially in vulnerable brains during development and aging. Sevoflurane exposure induces a spectrum of PND related changes. At the molecular level it activates the hypothalamic NKCC1, GABAA, and arginine vasopressin signaling cascade, which produces sustained upregulation of the hypothalamic pituitary adrenal axis and central inflammation, and can even yield cognitive deficits that are transmitted to offspring[113]. At the organelle level sevoflurane promotes p-dynamin-related protein 1 mediated mitochondrial fission and accelerates cognitive decline in Alzheimer model mice[85]. At the systems level sevoflurane disrupts gut microbiota homeostasis, reduces short chain fatty acid production, and impairs myelination. Butyrate supplementation reverses these effects[56]. Repeated sevoflurane exposure has also been linked to tau hyperphosphorylation and mislocalization, aberrant tubulin polyglutamylation, and loss of dendritic spines[97,114]. In open surgery models, isoflurane inhalation damages the structure and function of the BBB in mice, increases barrier permeability, and raises the probability of POD[115].

Translating these findings to the clinic remains challenging. A prospective cohort of older adults undergoing noncranial surgery found no significant association between sevoflurane dose, whether assessed by age adjusted minimum alveolar concentration fraction or area under the dose time curve, and either the severity or incidence of POD[116]. Another study reported that low concentration sevoflurane may be more detrimental than high concentration exposure for postoperative spatial cognition and survival of hippocampal CA1 neurons in aged rats[117]. These discrepant observations suggest that the cognitive effects of inhalational agents are shaped by a complex interplay among patient baseline status, surgical category, and depth of anesthesia monitoring. Rigorous large-scale studies are needed to clarify the clinical significance.

Intravenous anesthetics: A double-edged sword

Compared with inhalational agents, intravenous anesthetics exert complex effects on PND, displaying both protective and deleterious properties[118].

Dexmedetomidine: Widely recognized neuroprotection and anti-inflammatory actions: Dexmedetomidine, a highly selective alpha 2 adrenergic receptor agonist, has been extensively studied and acknowledged for perioperative neuroprotection[4,119]. Numerous clinical trials and preclinical studies have shown that dexmedetomidine lowers the incidence of POD and cognitive dysfunction[120,121]. Its protective mechanisms are multifaceted. First, it provides robust anti-inflammatory effects by suppressing the release of peripheral and central proinflammatory cytokines such as IL-6[121,122]. Second, it modulates the functions of neurons and glia. Single cell sequencing indicates that dexmedetomidine promotes a metabolic rebalance in neurons and attenuates neuroinflammation from a multicellular perspective[44]. Third, it enhances astrocytic release of brain-derived neurotrophic factor (BDNF), which mitigates anesthetic induced overactivation of alpha 5 GABAA receptor function caused by agents such as etomidate and thereby preserves synaptic homeostasis[94]. In addition, dexmedetomidine can reduce neuronal apoptosis by regulating the miR-381/early growth response 1/p53 axis[123]. Despite these benefits, clinicians should be mindful of potential adverse effects that include hypotension and bradycardia[122]. Notably, one study suggested that the cognitive benefits of dexmedetomidine may be independent of peripheral inflammation and are more closely associated with reductions in the neuronal injury marker S100β, implying a primary site of action within the CNS[124].

Ketamine and esketamine, anti-inflammatory promise amid psychotomimetic concerns: Ketamine and its S enantiomer esketamine are N-methyl-D-aspartate receptor antagonists that have attracted attention for rapid antidepressant and anti-inflammatory effects[125,126]. Clinical studies indicate that a single or short perioperative course of low dose esketamine can reduce early POD in older adults and alleviate anxiety and depressive symptoms[125,127]. These protective effects are thought to relate to suppression of systemic inflammation with reductions in IL-6 and S100β, as well as enhancement of BDNF production[127,128]. Nevertheless, the use of ketamine remains controversial. The effectiveness of ketamine in preventing PND varies across studies. A systematic review including 58 studies and 6830 patients reported that as many as 60% of studies found no cognitive benefit, and the effect may depend on surgical type, timing of administration, and dosage[126]. Moreover, ketamine carries psychotomimetic and psychiatric adverse effects. Although the incidence is lower with subanesthetic doses, these concerns still limit clinical adoption[125,126]. Preclinical work has further suggested that ketamine may impair the glymphatic like system in the brain, reduce clearance of metabolic waste, and thereby contribute to cognitive dysfunction[129]. Large, well designed randomized controlled trials are needed to define the benefit risk profile of ketamine based agents in the prevention and management of PND.

Propofol and other intravenous anesthetics, regulatory effects: Propofol is among the most commonly used intravenous anesthetics and exhibits bidirectional effects on cognition[118]. Several studies suggest neuroprotective potential. For example, propofol attenuates isoflurane induced neurotoxicity and cognitive impairment in fetal and offspring mice, possibly through anti-inflammatory and anti-apoptotic actions[130]. In contrast, other studies indicate that prolonged or repeated exposure during brain development can activate the NLRP3 and caspase 1 mediated pyroptosis pathway, trigger neuroinflammation and cognitive deficits[27], and disturb the excitatory inhibitory balance of hippocampal neurotransmission[131]. These dual effects underscore the need to carefully weigh dose, duration of exposure, and patient age in clinical use. Etomidate, another intravenous anesthetic, is favored for older or critically ill patients because it minimally affects hemodynamics, yet its suppression of adrenocortical function limits broader application. Combining etomidate with dexmedetomidine has been shown to improve postoperative cognitive outcomes and reduce neuronal injury markers S 100β and neuron specific enolase. This strategy offers a potential avenue to optimize anesthesia regimens for older patients[120].

Effects of analgesic strategies on cognitive function

Pain is a potent stressor that activates the hypothalamic pituitary adrenal axis and the sympathetic nervous system, induces a systemic inflammatory response, and serves as a major precipitating factor for PND[132]. Optimizing perioperative analgesia, particularly through multimodal and opioid sparing regimens, is therefore essential to attenuate stress and inflammation and to protect cognitive function[133].

Regional blocks, alleviating stress and inflammation: By interrupting nociceptive input at targeted sites, regional nerve blocks effectively reduce the surgical stress response and postoperative inflammation, thereby lowering the risk of PND. Multiple clinical trials have confirmed these benefits. In total hip arthroplasty, pericapsular nerve group blocks[134] and quadratus lumborum blocks[135] improved early postoperative cognition, as assessed by the Mini-Mental State Examination or Montreal Cognitive Assessment, and reduced the incidence of POCD. These effects correlate with significant reductions in plasma inflammatory markers such as HMGB1 and IL-6[134,135]. Similar findings have been reported in laparoscopic radical gastrectomy, where quadratus lumborum blocks attenuated postoperative inflammation and improved cognition in older adults[136]. In broader spinal procedures, epidural anesthesia combined with general anesthesia followed by postoperative epidural analgesia decreased systemic inflammatory responses and the occurrence of cognitive impairment compared with conventional general anesthesia with opioid-based analgesia[137]. Collectively, these studies highlight regional techniques that block nociception at the source as an effective strategy for preventing PND.

Non-opioid analgesics, anti-inflammatory and neuroprotective potential: Non-opioid analgesics, especially agents with anti-inflammatory properties, show considerable promise for the prevention and management of PND. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors suppress prostaglandin synthesis, provide analgesia, and directly mitigate inflammation. A large retrospective cohort study associated perioperative exposure to these drugs with a lower incidence of POD[138]. Parecoxib, a selective cyclooxygenase-2 inhibitor, reduced POD in a randomized controlled trial that enrolled patients with hyperlipidemia, a recognized risk factor for PND. The benefit was linked to inhibition of prostaglandin E2 synthesis, reductions in leukocyte counts, and improved postoperative pain control[139]. In preclinical models, ibuprofen improved cognition and inhibited systemic inflammation, glial activation, and tau phosphorylation[140]. These findings suggest that incorporating anti-inflammatory non-opioid agents into multimodal analgesia can reduce opioid requirements and may confer additional cognitive protection through direct modulation of inflammatory pathways.

NEW PERSPECTIVES AND THERAPEUTIC STRATEGIES FOR PND

Building on deeper insight into the pathophysiology of PND, with neuroinflammation at its core, investigators are actively exploring novel strategies for prevention and treatment. These approaches move beyond symptomatic management and aim to intervene at the source of pathology. They span targeted modulation of molecular pathways, restoration of systemic homeostasis, and nonpharmacologic interventions, offering renewed promise for clinical management.

Pharmacologic interventions targeting neuroinflammatory pathways

Directly targeting key molecules and signaling cascades within the neuroinflammatory cascade is one of the most active areas in drug development for PND.

Targeting DAMPs, TLRs, and the NLRP3 inflammasome: Because DAMPs act as the first signal that initiates postoperative inflammation, neutralizing DAMPs, for example using glycyrrhizin to inhibit HMGB1, or blocking their receptors, namely pattern recognition receptors, has become an attractive strategy[13]. TLRs, particularly TLR4 and TLR3, play pivotal roles in transducing signals from DAMPs and pathogen-associated molecular patterns. TLR4 inhibitors such as TAK-242[13], inhibitors of TLR3 double-stranded RNA complexes[141], and TLR7 antagonists that block the proinflammatory effect of let-7b[109] have reduced neuroinflammation and improved cognition in preclinical studies. The NLRP3 inflammasome acts as an amplifier of inflammatory signaling. Inhibition of NLRP3 with agents such as MCC950 or blockade of its downstream effector caspase-1 with VX-765 alleviates propofol- or surgery-induced neuroinflammation and cognitive deficits[26,27] (Table 1). For example, intraperitoneal MCC950 attenuated activation of the hippocampal inflammasome and significantly reduced proinflammatory cytokine expression in surgical mice[142]. Atorvastatin has also shown neuroprotection by suppressing the NF-κB pathway and inhibiting NLRP3 activation[143] (Table 1).

Table 1 Summarize the research on the effects of some drugs and therapies on postoperative neurocognitive disorder.

Drugs/therapies	Target	Pathway	Effect	Ref.
MCC950	NLRP3	NLRP3 inflammasome pathway	Reduce the expression of pro-inflammatory cytokines and relieve neuroinflammation	[132]
Atorvastatin	NLRP3	NLRP3 inflammasome pathway, NF-κB pathway	Play a neuroprotective role	[133]
IL-6 blocking therapy	IL-6		Reduce the expression of proinflammatory cytokine IL-6 and play a neuroprotective role	[88]
Maraviroc	CCR5/cAMP response element binding protein/NLRP1	CCR5/cAMP response element binding protein/NLRP1 pathway	Reduce neuroinflammation and improve cognitive impairment	[135]
Celastrol	Caspase-3/gasdermin E	cGAS-STING signaling pathway	Improving cognitive performance of POCD mice	[96]
Melatonin	Matrix metalloproteinase-9	Inflammatory pathway	Reduce neuroinflammation and synaptic dysfunction, improve delirium like behavior	[45]
Lactic acid	SIRT1	SIRT1 pathway	Improve POCD	[136]
Resveratrol	SIRT1	SIRT1 pathway, NF-κB pathway	Regulate microtubule function	[21]
Nrf2 activator	Nrf2		Inhibit neuroinflammation, promote neurogenesis, and improve cognitive function	[20,70]
Irisin	Microglia		Reprogramming microglia as anti-inflammatory M2 phenotype to prevent POCD	[19]
Galantamine	Cholinesterase	Cholinergic anti-inflammatory pathway	Restore the function of astrocytes and synapses	[137]
Varenicline	Tau protein		Reduce tau protein mislocalization, DNA damage and neuronal apoptosis, and improve cognition	[138]
Ginsenoside Rg1		Endocytosis lysosomal pathway	Eliminating β-amyloid and alleviating cognitive and synaptic deficits in elderly POCD mice	[139]
Probiotics	NLRP3	NLRP3 inflammasome pathway	Reduce the incidence of POCD in elderly patients. Reduce the incidence of POCD in elderly patients	[51,52]
Extracellular vesicles			Deliver therapeutic molecules to achieve precise treatment of central lesion area	[43,59]
Intranasal insulin	P3R/glucose-regulated protein 75/voltage-dependent anion channel 1	Phosphoinositide 3-kinases/protein kinase B signaling pathway	Reduce the level of proinflammatory cytokines and play a neuroprotective role	[76,142]
Coenzyme Q10	Mitochondria		Alleviate memory deficits	[143]
WS635	Mitochondria		Reduce synaptic damage and mitochondrial dysfunction	[144]
Elamipretide	NLRP3	NLRP3 inflammasome pathway	Restore damaged mitochondrial and synaptic functions	[145]
Lomastatin			Improve synaptic defects of neurons	[146,147]
Electroacupuncture		Multiple pathways	Neuroprotective effect	[71,150-152]
Vagus nerve stimulation	Acetylcholine	Cholinergic anti-inflammatory pathway	Exert anti-inflammatory effect	[57]
Preoperative and postoperative intervention		PPAR-gamma coactivator-1α/brain-derived neurotrophic factor pathway	Improving cognitive and inflammatory status in aged mice	[153]
Environmental enrichment			Reduce cognitive impairment and neuroinflammation caused by anesthesia/surgery	[155-157]

IL: Interleukin; Nrf2: Nuclear factor erythroid 2 related factor 2; NLRP: Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein; NF-κB: Nuclear factor-κB; cGAS: Cyclic GMP-AMP; STING: Stimulator of interferon genes; PPAR: Peroxisome proliferator-activated receptor; POCD: Postoperative cognitive dysfunction; SIRT1: Sirtuin 1; CCR5: C-C chemokine receptor type 5.

Targeting specific cytokines and their signaling pathways, including IL-6, IL-17A, and C-C motif ligand 5: Given the central roles of selected cytokines in PND, precise targeting has substantial potential. IL-6 is considered a key proinflammatory mediator. In a delirium-related neuropathology model induced by ventilator-associated lung injury, anti-IL-6 or anti-IL-6 receptor antibodies markedly reduced neuronal apoptosis in the frontal cortex and hippocampus, suggesting neuroprotective effects of IL-6 blockade[98] (Table 1). IL-17A is another important cytokine. Genetic deletion or pharmacologic inhibition of IL-17A improved behavioral outcomes after sevoflurane exposure in neonatal mice and downregulated other inflammatory genes in the hippocampus[144]. The chemokine C-C motif ligand 5 and C-C chemokine receptor type 5 (CCR5) also contribute to microglial activation in POCD. The CCR5 antagonist maraviroc mitigated neuroinflammation, prevented dendritic spine loss, and improved cognition by inhibiting the CCR5-cAMP response element binding protein-NLRP1 pathway[145] (Table 1). These findings provide new targets for the development of more specific anti-inflammatory therapies.

Neuroprotective agents such as celastrol and melatonin: Agents with broad anti-inflammatory and neuroprotective properties have shown promise for PND. Celastrol, a natural compound isolated from Tripterygium wilfordii, exerts potent anti-inflammatory effects. It improved cognitive performance in mouse models of POCD by inhibiting the cGAS-STING pathway and reducing caspase-3 and gasdermin E dependent pyroptosis[106] (Table 1). Melatonin, an endogenous hormone that regulates circadian rhythm, also has strong antioxidant and anti-inflammatory actions. In aged mouse models of PND, melatonin preserved BBB integrity by suppressing matrix metalloproteinase-9 activation, thereby reducing neuroinflammation and synaptic dysfunction and improving delirium-like behaviors[51] (Table 1). These agents tend to act upstream or at multiple nodes of inflammatory signaling, which may yield broader protective effects than single-target drugs.

Modulating glial function and energy metabolism

Given the central roles of glial dysregulation and metabolic disturbance in PND, strategies that restore their homeostasis have become a focus of investigation.

Activating endogenous protective pathways such as SIRT1, Nrf2, and irisin: The body harbors multiple endogenous defense pathways. Their activation can enhance resistance to perioperative stress injury. Members of the SIRT family, including SIRT1 and SIRT3, are key regulators of metabolism and stress sensing. Lactate improves POCD by activating the SIRT1 pathway and exerting antioxidant and anti-inflammatory effects[146] (Table 1). Agents such as resveratrol also activate SIRT1 and thereby modulate the NF-κB pathway and microtubule function[21] (Table 1). Nrf2 is a principal transcription factor that drives antioxidant responses. Its activators, including the itaconate derivative 4-octyl itaconate and caffeic acid phenethyl ester, have effectively suppressed neuroinflammation, promoted neurogenesis, and improved cognition[20,80] (Table 1). Irisin, an exercise induced hormone, crosses the BBB and directly reprograms microglia toward an anti inflammatory M2 phenotype, which prevents POCD[19] (Table 1). These approaches share a common principle. They harness intrinsic cellular defenses to counteract pathological injury.

Modulating neurotransmitter systems with emphasis on cholinergic signaling: Imbalance of neurotransmission is a key feature of PND. Restoring homeostasis provides a direct route to cognitive improvement. The cholinergic system is closely linked to learning and memory and is impaired in PND. Surgery reduces acetylcholine release in the hippocampus, impairing astrocytic function and long-term potentiation. The cholinesterase inhibitor galantamine restores acetylcholine levels and synaptic function[147] (Table 1). In addition, perioperative administration of varenicline, a partial agonist of nicotinic acetylcholine receptors, mitigates mislocalization of tau, limits DNA damage and neuronal apoptosis, and improves cognition[148] (Table 1). These findings suggest that enhancing cholinergic signaling is a promising therapeutic direction for PND.

Potential of bioactive constituents from traditional Chinese medicine such as ginsenoside Rg1: Traditional Chinese medicine provides a rich source of neuroprotective compounds. Many constituents show multi target actions with low toxicity and have demonstrated considerable promise in PND research. Ginsenoside Rg1, a major active component of ginseng, alleviates cognitive and synaptic defects in aged mouse models of POCD by promoting microglial clearance of amyloid beta through the endocytosis lysosome pathway[149] (Table 1). Plant derived flavonoids such as tamarixetin[76] and naringenin[102], as well as honokiol[82], berberine[150], and chlorogenic acid[151], have improved PND like phenotypes in preclinical models through anti-inflammatory and antioxidant mechanisms and by regulating mitophagy. These studies highlight natural products as valuable resources for developing safe and effective interventions against PND.

Interventions that restore systemic homeostasis

Because PND represents a CNS manifestation of organism-wide dysregulation, strategies that rebalance systemic homeostasis have distinctive therapeutic value.

Modulating the gut microbiota, probiotics and fecal microbiota transplantation: Targeting the gut brain axis is an emerging and promising approach for the prevention and treatment of PND[1]. Clinical studies have shown that perioperative administration of probiotic formulations can markedly reduce the incidence of POCD in older adults[57]. Animal experiments support this concept. Probiotics alleviate sevoflurane-induced dysbiosis and inhibit activation of the NLRP3 inflammasome pathway[58] (Table 1). Beyond probiotics, other microbiota-directed strategies such as supplementation with short-chain fatty acids including butyrate[56] or fecal microbiota transplantation also show considerable potential, although applications of the latter in PND require further investigation[6].

Therapeutic applications of extracellular vesicles: Extracellular vesicles function both as conveyors of pathological information in PND and as engineerable carriers for therapy[65] (Table 1). Their intrinsic tropism and capacity to traverse the BBB make them attractive vehicles for delivering therapeutic cargos. For example, vesicles can be loaded with neuroprotective or anti-inflammatory microRNAs such as miR-26a-5p[48], as well as with drugs or proteins, to achieve precise treatment of affected brain regions. This acellular strategy avoids the risks associated with direct cell transplantation while preserving the specificity of intercellular communication, thereby opening a nano-delivery route for PND therapy[65].

Intranasal delivery, exemplified by insulin: Intranasal administration is a noninvasive route that bypasses the BBB and delivers agents directly to the CNS. Insulin exerts important neurotrophic and metabolic regulatory effects in the brain. Repeated intranasal insulin has been shown to significantly lower the incidence of POD in older patients[152]. Mechanistically, intranasal insulin modulates the calcium transport protein complex on mitochondria-associated endoplasmic reticulum membranes, namely inositol 1,4,5 trisphosphate receptor, glucose-regulated protein 75, and voltage-dependent anion channel 1, stabilizes mitochondrial function, activates the phosphoinositide 3-kinases and AKT signaling cascade to promote neuroprotection, and lowers circulating pro-inflammatory cytokine levels[86,152] (Table 1). This approach provides a paradigm for delivering large peptide therapeutics to CNS disorders.

Bioactive molecules that regulate mitochondrial and synaptic function: The development of PND is closely linked to surgery-induced mitochondrial dysfunction and synaptic injury, which represent two critical pathogenic nodes. In targeted intervention studies, the mitochondrial bioenergetic enhancer coenzyme Q10 has been shown to ameliorate memory deficits by restoring synaptic protein expression after anesthesia and by optimizing mitochondrial energy supply[153] (Table 1). A novel compound designated WS635 attenuates synaptic damage and mitochondrial impairment in hippocampal and cortical tissues after surgery in mice[154] (Table 1). Notably, although WS635 is structurally related to cyclosporine A, it lacks immunosuppressive activity, which broadens its translational potential for PND. The synthetic mitochondria-targeted antioxidant tetrapeptide elamipretide exerts multiple actions. It repairs damaged mitochondrial and synaptic function and suppresses NLRP3 inflammasome-mediated pyroptosis[155] (Table 1). The antihistamine clemastine has also shown promise for PND. Evidence indicates that it promotes remyelination and restores synaptic function[156,157], and recent animal studies demonstrate enhanced neuronal remyelination and improved synaptic deficits in mice exposed to isoflurane anesthesia and laparotomy[158] (Table 1). Taken together, therapies that prioritize restoration of mitochondrial function and repair of synaptic injury show encouraging prospects in PND. The development of agents without immunosuppressive activity and the use of mitochondria-targeted antioxidants offer new avenues that may expand applicability and reduce the risk of adverse effects[159].

Exploration of nonpharmacological interventions

Nonpharmacological strategies are attracting growing attention in the comprehensive management of PND because of their favorable safety profile and minimal adverse effects.

Electroacupuncture and vagus nerve stimulation: Electroacupuncture, a refined form of traditional acupuncture, is increasingly understood in the context of PND prevention and treatment (Table 1). Evidence indicates that electroacupuncture confers neuroprotection through several mechanisms. It suppresses activation of the NLRP3 inflammasome, thereby reducing neuroinflammation and damage to the BBB[160]. It rebalances the gut microbiota, limits microglial activation, and reverses excessive dendritic spine pruning[161]. It activates transcription factor EB mediated autophagy lysosomal pathways to facilitate Aβ clearance[162]. It also preserves telomerase reverse transcriptase function to limit oxidative stress[81]. Vagus nerve stimulation represents another neuromodulatory anti-inflammatory approach. The vagus nerve is a principal conduit between the CNS and peripheral immunity. Activation of the cholinergic anti-inflammatory pathway through vagal stimulation can effectively restrain systemic inflammation. A minimally invasive percutaneous vagus nerve stimulation technique was developed and shown to reduce lipopolysaccharide induced systemic and hippocampal inflammatory responses and to improve cognition[63] (Table 1).

Rehabilitation training and environmental enrichment: Preoperative physical and cognitive prehabilitation and postoperative environmental interventions are critical for improving physiological reserve and resilience to perioperative stress. A five-week preoperative resistance training program improved baseline cognition and inflammatory status in aged mice and subsequently mitigated postoperative neuroinflammation, enhanced mitochondrial health, and promoted synaptic plasticity through activation of the hippocampal peroxisome proliferator-activated receptor-gamma coactivator-1α and BDNF pathway[163] (Table 1). Notably, the benefits of exercise appear transmissible through plasma. Transfusion of plasma from exercised mice to sedentary mice conferred protection against PND, an effect associated with activation of hippocampal cholinergic circuits and BDNF and tropomyosin receptor kinase B signaling[164]. Environmental enrichment, such as providing abundant olfactory stimuli before surgery or housing with familiar cage mates after surgery, has also been shown to attenuate anesthesia and surgery induced cognitive impairment and neuroinflammation[165-167] (Table 1). These nonpharmacological measures underscore the importance of lifestyle and environmental optimization to strengthen cognitive reserve and resilience, and they offer holistic and individualized avenues for PND prevention.

CONCLUSION

Over the past decade, research on the pathophysiology of PND has advanced substantially, and a complex regulatory network centered on neuroinflammation with multiple factors, pathways, and layers has come into clearer focus. This review is based on a literature search of PubMed and Web of Science using terms including “Postoperative Neurocognitive Disorders”, “NIS”, “Microglia-Neuron Interactions”, “Neuroinflammation”, “Anesthetic Modulation”, and “Complement System”. Relevant original studies and reviews published in the past two decades were screened and synthesized. While this review focuses on PND, some studies on the underlying mechanisms of PND has been informed by studies utilizing POCD mouse models. Given the significant overlap in pathophysiology, including neuroinflammation and cognitive deficits induced by surgical procedures and anesthetic exposure, evidence from POCD models can be generalized to provide valuable insights into the broader context of PND. Therefore, despite differences in terminology, the findings from POCD models contribute significantly to our understanding of PND.

Surgical injury and anesthetic exposure initiate peripheral inflammatory signals that reach the brain through BBB disruption, gut-brain axis imbalance, and circulating cytokines, activating microglia- and astrocyte-driven neuroinflammation. Resulting glial dysfunction, including pro-inflammatory polarization, metabolic disturbance, mitochondrial impairment, oxidative stress, and synaptic disruption, contributes to neuronal vulnerability. Emerging epigenetic mechanisms such as noncoding RNAs and histone modifications may further explain the persistence of these pathological changes[8,44,107]. Moreover, aging is also an important independent risk factor for PND.

The dual edged effects of anesthetics indicate that perioperative management is not a simple matter of inhibition or excitation but a finely tuned balance[23]. Current evidence highlights the importance of reducing stress and inflammation through agents such as dexmedetomidine and through regional anesthesia and analgesia[4,137]. Guided by mechanistic insights, emerging strategies, including targeting inflammatory mediators like NLRP3 and IL-6, activating protective pathways such as SIRT1 and Nrf2, modulating the microbiota, enhancing mitochondrial and synaptic function, and applying nonpharmacological approaches such as electroacupuncture and prehabilitation, are shifting PND management toward more precise and multidimensional interventions[8,19,80,152,160].

Despite substantial progress in preclinical research, clinical translation remains difficult. Most findings require validation in large, well-designed randomized controlled trials to confirm safety and efficacy[2,8,126]. Developing reliable biomarkers for early detection, risk stratification, and treatment monitoring is equally essential for advancing precision medicine[13,168,169]. Future studies should integrate multi-omics data to define subtype-specific pathways shaped by age, comorbidities, surgical type, and microbiota status[41,170]. Advancing novel delivery strategies, restoring mitochondrial and synaptic function, and optimizing perioperative neuroprotection through anesthetic management and nonpharmacological approaches will also be essential. Ultimately, interdisciplinary collaboration bridging mechanistic neurobiology with clinical practice is crucial for translating preclinical advances into effective prevention and treatment strategies for PND.