The NLRP3 Inflammasome: A Central Mediator in Sevoflurane-Induced Neurotoxicity and A Potential Target for Neuroprotection

Abstract

The neurological influence of the widely used inhalational anesthetic sevoflurane presents a context-dependent paradox, manifesting as either neurotoxicity or neuroprotection. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a central mediator of neuroinflammation and pyroptosis, has emerged as a key molecular underlying these divergent outcomes. This review integrates current evidence on the role of the NLRP3 inflammasome in the bidirectional effects of sevoflurane, offering a mechanistic framework to guide neuroprotective strategies in perioperative medicine. Analysis reveals that in vulnerable states such as Alzheimer’s disease and postoperative cognitive dysfunction, sevoflurane-induced activation of the NLRP3 inflammasome contributes to neurotoxicity and cognitive decline. This process engages multiple CNS cell types, with microglia serving as the primary source of inflammasome-dependent pyroptosis, astrocytes amplifying the inflammatory response, and neurons representing the ultimate targets of injury. Key upstream triggers include mitochondrial dysfunction, oxidative stress, impaired autophagy, and disruption of ion homeostasis, with blood-brain barrier breakdown and gut microbiota dysbiosis further reinforcing this pathological cascade. Conversely, under specific pathological conditions, including cerebral ischemia and neuropathic pain, sevoflurane can suppress NLRP3 activation, indicating that its ultimate effect is determined by the host cellular stress landscape and the net balance of concurrently engaged signaling pathways. Pharmacological inhibition of the NLRP3 pathway demonstrates robust neuroprotective efficacy in preclinical models. Nevertheless, a substantial translational gap remains due to challenges in drug specificity, blood-brain barrier penetration, and safety concerns associated with prolonged suppression of innate immunity. In conclusion, the NLRP3 inflammasome serves as a pivotal integrator of sevoflurane context-dependent neurological effects. The current research landscape remains fragmented and predominantly correlative, relying on heterogeneous experimental models. Future studies should shift from descriptive phenomenology toward identifying decisive molecular switches that govern NLRP3 activation or suppression following sevoflurane exposure. Such insights are indispensable for developing context-dependent combinatorial therapeutic strategies and for bridging the translational gap through validated biomarkers and clinically relevant models, thereby advancing the objective of precision anesthesiology.

Background

Sevoflurane is among the most widely used inhalational anesthetics, owing to its rapid onset and favorable hemodynamic profile. Nevertheless, its neurological effects exhibit a paradoxical duality, manifesting as either neurotoxicity or neuroprotection depending on the specific context [1–5]. In the reviewed preclinical literature, neurotoxicity is typically characterized by impaired cognitive performance in behavioral tasks, reduced synaptic protein expression, or neuronal loss [6–9], whereas neuroprotection refers to the preservation or restoration of these functional and structural parameters [10–12]. A critical and unresolved question is whether the neurotoxicity observed particularly in the developing or aging brain reflects an inherent risk of exposure or is instead by variables such as dose and duration [13–18]. Moreover, repeated exposures may confer distinct risks compared to single exposures [9, 19, 20]. Conversely, sevoflurane can paradoxically exert neuroprotective effects under certain pathological conditions such as cerebral ischemia [4, 5, 12, 21, 22]. This observation suggests that the ultimate neurological impact of sevoflurane depends on the interplay between anesthetic exposure and the patient’s underlying pathophysiological state.

The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a central mediator of neuroinflammation and pyroptosis and has emerged as a pivotal node in this dichotomy [23, 24]. Activation of the NLRP3 inflammasome triggers caspase-1-mediated maturation of pro-inflammatory cytokines and gasdermin-D-dependent pyroptosis, both of which are processes implicated in diverse neurological disorders [23, 25, 26]. Intriguingly, sevoflurane has been reported to both activate and suppress the NLRP3 pathway. This bidirectional modulation mirrors its paradoxical biological effects and suggests that the NLRP3 inflammasome may function as a molecular switch whose activation state influences neurological outcomes following exposure [4, 5, 21, 22, 27–29]. However, it remains unclear whether NLRP3 functions as the direct mediator of sevoflurane-induced neurotoxicity or whether its inhibition merely represents a downstream consequence of parallel neuroprotective signaling.

Accordingly, this review addresses four interrelated objectives. First, we outline the fundamental biology of the NLRP3 inflammasome and its role as a key integrator of neuroimmune signaling. Second, we examine evidence on how sevoflurane modulates this pathway to promote neurotoxicity in conditions such as Alzheimer’s disease (AD) and postoperative cognitive dysfunction. Third, we explore the paradoxical context in which sevoflurane inhibits NLRP3 activation to confer neuroprotection, particularly under ischemic or inflammatory stress. Finally, we evaluate the translational potential of targeting the NLRP3 inflammasome, considering preclinical inhibitors, current challenges, and future directions for developing safe and effective neuroprotective strategies in anesthesia. By integrating these perspectives, this review aims to provide a comprehensive overview of the NLRP3 inflammasome as a crucial molecular switch underlying the dual neurological effects of sevoflurane.

Biological Function of NLRP3 Inflammasomes

The NLRP3 inflammasome is a crucial cytosolic sensor complex that links innate immunity to neuroinflammation [23, 24, 30, 31]. In the central nervous system (CNS), it serves as a molecular platform for detecting cellular stress and for orchestrating inflammatory signaling in microglia, astrocytes, and neurons [27–29, 32]. Dysregulation of this pathway has been implicated in a broad spectrum of neurological disorders, including AD, Parkinson’s disease (PD), and postoperative cognitive dysfunction (POCD) [23, 25, 26].

Structure and Core Components

The canonical NLRP3 inflammasome comprises three essential components, which are the sensor protein NLRP3, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and the effector enzyme caspase-1 [23, 33]. Upon activation, NLRP3 oligomerizes via its nucleotide-binding domain (NACHT) and recruits ASC through pyrin–pyrin (PYD–PYD) interactions [34, 35]. ASC then recruits caspase-1 through CARD–CARD binding, leading to caspase-1 autoactivation [23, 33, 36]. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature proinflammatory forms and also cleaves gasdermin D (GSDMD). This cleavage generates N terminal fragments that oligomerize to form membrane pores that initiate pyroptotic cell death [37, 38]. This cascade amplifies neuroinflammatory signaling and link innate immunity to neuronal injury.

Activation Mechanisms

NLRP3 activation generally proceeds through two coordinated steps, priming and triggering. The priming step involves transcriptional upregulation of NLRP3 and pro-IL-1β via NF-κB signaling and is typically initiated by stimulation of Toll-like receptors (TLRs) or IL-1 receptor [34, 35, 37]. The triggering step integrates diverse stimuli such as potassium efflux, calcium influx, mitochondrial dysfunction, and lysosomal rupture which collectively induce conformational activation of NLRP3 [38, 39].

Upstream activators fall broadly into two categories. Damage-associated molecular patterns (DAMPs), such as extracellular ATP, uric acid crystals, and reactive oxygen species (ROS), are released during cellular stress or injury [34, 35]. Pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS) and double-stranded RNA, activate pattern-recognition receptors to initiate inflammasome assembly [34, 40].

Mitochondrial impairment plays a critical role in neuronal contexts. ROS overproduction, together with dissociation of thioredoxin-interacting protein (TXNIP) from thioredoxin and release of mtDNA, can directly trigger NLRP3 activation [8, 41–45]. Similarly, potassium efflux and calcium dysregulation act as secondary messengers that link sevoflurane exposure and metabolic perturbations to inflammasome assembly (Fig. 1) [38, 39]. Through these convergent pathways, NLRP3 functions as a molecular integrator of metabolic, oxidative, and inflammatory stresses.

Fig. 1.

Priming and activation of the NLRP3 inflammasome under sevoflurane exposure. The activation of the NLRP3 inflammasome involves two steps. Priming: PAMPs, DAMPs, or cytokines engage receptors such as TLRs, TNFRs, and IL-1R, activating NF-κB to induce transcription of NLRP3, pro-IL-1β, and pro-IL-18. Sevoflurane can enhance this process via TLR–NF-κB and p38/GSK3β signaling, as well as NF-κB–SP1–PI3K/Akt/mTOR activation that suppresses autophagy. Activation: Various stimuli—including K⁺ efflux, Ca²⁺ flux, ROS accumulation, lysosomal rupture, and ox-mtDNA release—promote inflammasome assembly. Sevoflurane contributes by altering membrane potential to drive Ca²⁺ influx, inhibiting mitochondrial PRDX3 to increase ROS, inducing mPTP opening with ox-mtDNA release, activating the TXNIP–NLRP3 interaction and the cGAS–STING pathway, and stimulating HDAC6–HSP90/HSP70. Downstream events: Oligomerized NLRP3 recruits ASC and pro-caspase-1, leading to caspase-1 activation, IL-1β/IL-18 maturation, and GSDMD pore formation that drives pyroptosis. Caspase-8/3-mediated GSDME cleavage provides an additional pore-forming pathway. Sevoflurane also triggers extranuclear release of HMGB1, which acts as a DAMP to amplify sterile inflammation. Abbreviations: NLRP3 NOD-, LRR-, and pyrin domain-containing protein 3; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TLR, Toll-like receptor; TNFR, tumor necrosis factor receptor; IL-1R, interleukin-1 receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL-1β, interleukin-1β; IL-18, interleukin-18; SP1, specificity protein 1; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; mTOR, mechanistic target of rapamycin; K⁺, potassium ion; Ca.²⁺, calcium ion; ROS, reactive oxygen species; PRDX3, peroxiredoxin-3; mPTP, mitochondrial permeability transition pore; ox-mtDNA, oxidized mitochondrial DNA; TXNIP, thioredoxin-interacting protein; cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; HDAC6, histone deacetylase 6; HSP90/HSP70, heat shock protein 90 / heat shock protein 70; ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase activation and recruitment domain; Caspase-1/3/8, cysteine-aspartic protease-1/3/8; GSDMD, gasdermin D; N-GSDMD, N-terminal fragment of gasdermin D; HMGB1, high-mobility group box 1

Figure 1 summarizes the canonical NLRP3 inflammasome activation cascade and identifies the principal nodes at which sevoflurane intersects with this pathway. During priming, sevoflurane may potentiate NF-κB‑driven transcription through p38/GSK3β and SP1/PI3K/Akt/mTOR signaling [46–48]. During triggering, sevoflurane exacerbates potassium efflux, calcium influx, peroxiredoxin-3 (PRDX3) suppression, mitochondrial permeability transition pore opening with ox‑mtDNA release, and TXNIP dissociation. These events collectively promote NLRP3 oligomerization [8, 41–45, 49]. Downstream, caspase‑1 cleaves GSDMD or GSDME to initiate pyroptosis, and the subsequent release of high-mobility group box 1 (HMGB1) propagates sterile inflammation in a feed‑forward manner [50–52]. The following sections examine how sevoflurane engages these nodes to produce the opposing outcomes of neurotoxicity and neuroprotection.

Downstream Effects and Crosstalk with Neuroinflammation

Upon activation, the NLRP3 inflammasome drives caspase-1-dependent cleavage of pro-IL-1β and pro-IL-18. This cleavage promotes their secretion and amplifies neuroinflammatory cascades [10, 53]. Concurrently, caspase-1 cleaves GSDMD to generate N-terminal fragments that oligomerize and insert into the plasma membrane to form pores [37, 38, 54]. These pores facilitate the release of mature IL-1β and IL-18, disrupt cellular ion homeostasis, and may ultimately cause osmotic lysis, thereby amplifying inflammatory signals [37, 54]. The pyroptotic release of DAMPs such as HMGB1 and ATP further propagates inflammation and promotes microglial activation [50–52].

In the CNS, NLRP3 activation is implicated in the pathophysiology of numerous disorders. In AD, β-amyloid and tau aggregates can trigger NLRP3 activation and sustain chronic microglial inflammation [55, 56]. In PD, α-synuclein aggregates initiate a similar cascade that exacerbates dopaminergic neuronal loss [57]. Conversely, regulated or transient NLRP3 activation may support protective immune clearance under specific stress conditions, highlighting its dual role in neuroimmune homeostasis [4, 5, 21, 22].

From a therapeutic standpoint, pharmacological inhibition of NLRP3 or GSDMD-mediated pyroptosis has shown neuroprotective potential in animal models [7, 9, 54, 58–64]. Meanwhile, natural compounds such as resveratrol and curcumin modulate inflammasome activity through antioxidative and autophagic pathways [29, 39, 54, 58, 60, 65, 66].

In summary, the NLRP3 inflammasome acts as both a sensor and an effector hub that connects innate immunity to neuronal viability. Nevertheless, the precise mechanisms governing its activity in the nervous system, particularly the dynamic interactions among neurons, microglia, and astrocytes, warrant further investigation to clarify its contributions to neurodegeneration and neuroprotection.

The Mechanisms of NLRP3 Inflammasome in Sevoflurane-Related Neurotoxic Diseases

The context-dependent modulation of neuroinflammation and pyroptosis by sevoflurane is fundamentally governed by the interplay between exposure parameters and host factors. Key exposure parameters include dose and duration, while host factors encompass age and baseline inflammatory status. For example, neurotoxicity exhibits a non-linear dependence on exposure duration [13], and repeated exposures confer greater risk through sequential tau phosphorylation [19]. Host age and baseline inflammatory status are critical modifiers. Together, these variables regulate the activation threshold of pathways such as NLRP3 and thereby influence whether sevoflurane promotes neurotoxicity in AD and POCD or exerts effects in models of ischemia or neuropathic pain.

Alzheimer’s Disease

AD is an irreversible neurodegenerative disorder characterized by the deposition of β-amyloid plaques and the formation of neurofibrillary tangles due to tau hyperphosphorylation. Clinically, it manifests as progressive cognitive decline and memory impairment [55, 67]. Its pathogenesis is multifactorial and involves genetic predisposition, oxidative stress, and neuroinflammation. Currently, no curative treatment exists for AD, and drug development efforts focus primarily on targeting abnormal protein aggregation and modulating synaptic function [68].

Sevoflurane exacerbates AD pathology through mechanisms that interact with genetic vulnerability. Sevoflurane-induced caspase-1 dependent GSDMD cleavage in BV2 microglia, an effect abolished by NLRP3 or caspase-1 knockout [54]. A clinically relevant exposure (3% for 6 h) in APP/PS1 models triggers tau-related enzymes dysregulation and a transgene-specific increase in soluble Aβ levels [54]. These transient enzymatic changes can serve as a trigger for the NLRP3 inflammasome and promote caspase-1-dependent GSDMD cleavage and microglial pyroptosis. Although the initial insult is acute, the resulting cellular damage promotes sustained Aβ deposition, chronic release of pro-inflammatory cytokine, and reduced levels of brain-derived neurotrophic factor (BDNF). This process is driven upstream by mitochondrial oxidative stress and impaired autophagic clearance [69]. These pathological changes manifest as significant cognitive deficits, including prolonged escape latency in the Morris water maze and impaired recognition in novel object tests, which correlate with hippocampal neuronal loss and synaptic degradation [54, 69]. Collectively, these findings effectively bridge acute anesthetic exposure to the progressive and chronic pathology of AD.

In summary, activation of NLRP3 inflammasomes, induction of pyroptosis, and dysregulation of tau phosphorylation are key mechanisms by which sevoflurane may promote neuroinflammation and neurodegeneration in AD.

Postoperative Cognitive Dysfunction

Extensive preclinical research has examined the molecular and cellular mechanisms by which sevoflurane exposure contributes to POCD through activation of the NLRP3 inflammasome and neuroinflammatory cascades. Sevoflurane exposure combined with surgical stress triggers a multistep neuroinflammatory process characterized by oxidative stress, microglial and astrocytic activation, blood-brain barrier (BBB) disruption, and subsequent neuronal injury [70]. The neurotoxic outcomes are evident at multiple levels. Behavioral endpoints include prolonged escape latency and fewer platform crossings in the Morris water maze, reduced discrimination index in novel object recognition, and impaired freezing behavior in fear conditioning [39, 52, 58, 60]. Some studies further report increased anxiety-like behavior, reflected by reduced open-arm time in the elevated plus maze and decreased center time in the open field [9, 46]. Upstream triggers that converge on NLRP3 activation in this context include sevoflurane-induced mitochondrial dysfunction with ROS overproduction, intracellular potassium efflux, calcium dysregulation, and impaired autophagic clearance of damaged organelles. Structural endpoints in hippocampal tissue, sevoflurane increases TUNEL positive neurons, upregulates of NLRP3, cleaved caspase-1, IL-1β, and GSDMD-N, elevates reactive oxygen species and malondialdehyde levels, and mitochondrial swelling with cristae loss [4, 7, 29, 60, 65, 71]. These behavioral and structural alterations provide a mechanistic basis for sevoflurane-induced cognitive deficits.

Microglia play a central role in this process. Sevoflurane exposure is associated with mitochondrial dysfunction and excessive ROS generation, both of which are established upstream signals for NLRP3 inflammasome activation [66, 70]. Impaired autophagic flux, indicated by decreased LC3-II/I ratios and increased p62 accumulation, correlates with reduced clearance of damaged mitochondria and heightened oxidative stress [39, 60]. Moreover, sevoflurane suppresses histone lactylation, notably at H3K18. This suppression reduces expression of the m6A reader YTHDF3 and consequently downregulating translation of the antioxidant enzyme PRDX3, thereby creating a permissive environment for ROS-driven NLRP3 activation [49].

In addition to ROS-mediated priming, several intracellular signaling pathways converge to promote NLRP3 activation in microglia. The P2X4R pathway facilitates ATP-dependent calcium influx and upregulates the Kv1.3 potassium channel, thereby enhancing inflammasome assembly [50–52, 72]. mtDNA leakage into the cytoplasm following sevoflurane-induced mitochondrial damage triggers the cyclic cGAS–STING axis, which amplifies NLRP3 activation [29, 73]. This process is reinforced by upregulation of SENP7, which deSUMOylates and activates cGAS [73]. Similarly, extranuclear HMGB1 released from damaged neurons binds to TLR4 and activates NF-κB signaling to transcriptionally upregulate NLRP3 [50]. The HDAC6–HSP90/HSP70 axis also modulates inflammasome assembly, wherein sevoflurane-stimulated HDAC6 deacetylates HSP90, alters its interaction with NLRP3, and facilitating conformational maturation of the inflammasome complex [74].

Activated NLRP3 inflammasomes promote Caspase-1-dependent cleavage of pro-IL-1β and pro-IL-18 into their active forms, which elicits a robust inflammatory response [60]. Concurrently, GSDMD mediates pyroptotic cell death in microglia and facilitates the release of secondary DAMPs such as HMGB1 and ATP, thereby perpetuating neuroinflammation [50, 60, 74]. The released IL-1β and other factors activate surrounding astrocytes primarily through the p38/MAPK/GSK3β signaling pathway. This activation shifts astrocytes to a reactive state characterized by the release of additional pro-inflammatory cytokines and impairment of their normal supportive functions for neurons, which exacerbating synaptic dysfunction and neuronal injury [46].

Neurons are not passive targets in this process and actively participate in inflammasome-mediated pathology [58, 64]. Sevoflurane can directly activate neuronal NLRP3 inflammasomes, promoting Caspase-1-dependent pyroptosis via the NEK7–SNHG3–NLRP3 axis [65, 75]. Similar to microglia, sevoflurane increases neuronal ROS and malondialdehyde levels and subsequently activates the NF-κB pathway, which further upregulates NLRP3 expression in neurons [76, 77]. Sevoflurane also inhibits neuronal autophagy, as indicated by a reduced LC3-II/I ratio and increased p62 levels [78]. In addition, Sevoflurane regulates neuronal NLRP3 through histone modifications such as deacetylation, an effect that can be reversed by HDAC inhibitors like SAHA [19]. Sevoflurane-induced oxidative stress and NF-κB activation upregulate neuronal NLRP3 expression, while impaired autophagy via SP1/PI3K/Akt/mTOR activation and AMPK/SIRT1 suppression leads to accumulation of damaged mitochondria and persistent ROS signaling [47, 48]. Epigenetic mechanisms further modulate these processes. Histone deacetylation suppresses neuroprotective gene expression, whereas YTHDF1-mediated m6A modification stabilizes CREB mRNA and enhancing CREB/BDNF signaling to support synaptic resilience [75, 79]. MicroRNA -mediated regulation of GPX4 also contributes to the epigenetic control of NLRP3 [80]. Finally, sevoflurane-induced hypermethylation of the clock gene PER2 suppresses its transcription, which reduced AKT pathway activity and enhanced NLRP3 inflammasome activation in microglia [81].

The integrity of the BBB is both a target and a critical amplifier within the NLRP3-centered inflammatory cascade. Sevoflurane-induced oxidative stress can directly damage brain microvascular endothelial cells. This damage downregulates tight junction proteins such as claudin-5, occludin, and ZO-1, and upregulating matrix metalloproteinases (MMP-2/9), thereby increasing BBB permeability [11, 14, 82]. The resulting breach enables peripheral cytokines, endotoxins, and immune cells to enter the CNS parenchyma [69, 79]. These infiltrating factors act as secondary stimuli that activate glial pattern-recognition receptors and amplify sevoflurane-initiated NLRP3 activation [14]. Conversely, NLRP3 activation may further impair the BBB through glial-derived cytokines that exacerbate endothelial dysfunction. Additionally, age-related baseline BBB hyperpermeability lowers the threshold for peripheral inflammatory signaling, which renders the aging brain more susceptible to sevoflurane-induced NLRP3 activation [14, 15, 83].

Beyond direct CNS mechanisms, sevoflurane may also establish a permissive systemic environment that potentiates neuroinflammation via the gut-brain axis. Emerging evidence suggests that sevoflurane exposure can induce gut microbiota dysbiosis and compromise intestinal barrier integrity [6, 9]. This disruption promotes increased translocation of bacterial endotoxins such as LPS into the circulation. Systemically elevated LPS provides a potent priming signal for immune cells, including CNS microglia, and thereby lowers the threshold for NLRP3 inflammasome activation triggered by direct anesthetic exposure in the brain [9, 84]. Recent work shows that extracellular vesicles from Akkermansia muciniphila can inhibit NLRP3 activation, restore intestinal tight-junction integrity, and improve POCD in aged mice, which highlights the gut-brain-immune interface as a potential therapeutic target [84]. Thus, gut-derived systemic inflammation may act as a critical amplifier within the neuroimmune network and contribute to the chronicity and severity of POCD.

Integration into a cell-type-specific neuroimmune amplification network. The molecular events described above converge into a hierarchical multicellular cascade as illustrated in Fig. 2. Within this network, microglia serve as the principal sensors and the primary source of NLRP3 inflammasome dependent pyroptosis They initiate the neuroinflammatory response through the release of IL-1β, IL-18, and DAMPs [60, 66, 70]. Astrocytes respond to this altered milieu by adopting a reactive phenotype marked by the loss of homeostatic functions and the amplification of proinflammatory signaling, which indirectly compromises neuronal integrity [46]. Hippocampal neurons represent the final targets of this integrated stress. They are vulnerable to both direct activation of intrinsic neuronal NLRP3 pathways and to the cytotoxic environment generated by activated glia [58, 64]. The resulting synaptic injury and impaired plasticity manifest as the learning and memory deficits characteristic of POCD. This central inflammatory loop is further reinforced by systemic contributions from increased BBB permeability and a primed gut-brain axis, which together sustain a pathological feed forward cycle of microglial activation [6, 9, 14, 15, 83].

Fig. 2.

Sevoflurane-driven NLRP3-centered neuroimmune amplification network leads to neuroinflammation and POCD. Multilayered mechanisms and intercellular/organ interactions underlie sevoflurane-induced POCD. In astrocytes, sevoflurane activates the p38/MAPK/GSK3β pathway, thereby priming and activating the NLRP3 inflammasome, amplifying neuroinflammation and indirectly impairing neuronal function. Microglia act as central amplifiers of this process. Sevoflurane induces mitochondrial dysfunction and impaired autophagy, leading to ROS accumulation and mtDNA release; simultaneously, it upregulates the purinergic receptor P2X4R to enhance ATP-mediated Ca²⁺ influx, activates the cGAS–STING and HMGB1–TLR4/NF-κB pathways, and modulates inflammasome conformation via the HDAC6–HSP90/HSP70 axis in microglia. Hippocampal neurons, highly vulnerable to neuroinflammatory stress, are exposed to a cytokine storm comprising IL-1β, IL-18, and TNF-α released from glia and challenged by intrinsic ROS, defective autophagy, and epigenetic dysregulation. They undergo pyroptotic activation, mitochondrial injury, and synaptic plasticity loss, leading to hippocampus-dependent learning and memory impairments. In parallel, inflammatory cytokines, ROS, and HMGB1 compromise BMECs, causing tight-junction disruption and endothelial pyroptosis/apoptosis, thereby increasing BBB permeability and facilitating the entry of peripheral LPS, cytokines, and other DAMPs that further fuel glial activation. Beyond the CNS, sevoflurane disrupts gut microbial homeostasis, leading to barrier impairment, LPS translocation, and SCFA depletion. These systemic inflammatory signals reach the brain via circulation and reciprocally interact with central neuroinflammation, forming a vicious feed-forward loop. In summary, sevoflurane drives an NLRP3-centered neuroimmune amplification network involving astrocytes, microglia, hippocampal neurons, the BBB, and the gut–brain axis, ultimately leading to neuroinflammation, synaptic dysfunction, and POCD. Abbreviations: POCD, postoperative cognitive dysfunction; ROS, reactive oxygen species; mtDNA, mitochondrial DNA; cGAS, cyclic GMP–AMP synthase; STING, stimulator of interferon genes; HMGB1, high mobility group box 1; TLR4, Toll-like receptor 4; NF-κB, nuclear factor-κB; HDAC6, histone deacetylase 6; HSP90/70, heat shock protein 90/70; BMECs, brain microvascular endothelial cells; BBB, blood-brain barrier; LPS, lipopolysaccharide; DAMPs, damage-associated molecular patterns; SCFAs, short-chain fatty acids

Collectively, these preclinical findings indicate that sevoflurane exposure combined with surgical stress can prime and activate the NLRP3 inflammasome across multiple neural cell types. This process leads to microglial pyroptosis, astrocytic activation, neuronal injury, and synaptic dysfunction, all of which are molecular features associated with POCD. Furthermore, sevoflurane-induced gut microbiota dysbiosis may enhances intestinal permeability and promote LPS translocation into the systemic circulation, thereby establishing a gut–brain inflammatory loop that sustains NLRP3 activation and neuroinflammation.

Clinical investigations have built upon these preclinical mechanistic insights and support an association between sevoflurane anesthesia and POCD, particularly in vulnerable populations such as the elderly [16–18]. The clinical manifestations resemble those observed in animal models of POCD. Direct evaluation of neuroinflammatory pathways, including NLRP3 activation, is not feasible in patients. Nonetheless, the available clinical evidence links sevoflurane exposure to measurable cognitive decline and concurrent systemic inflammatory responses, as summarized in Table 1.

Table 1.

Summary of clinical studies comparing anesthetic regimens and their effects on postoperative cognitive outcomes

Author (year)	Design	Population	Comparison	Main findings	Conclusion
Micha G et al. (2016) [85]	RCT	Elderly, non-cardiac (> 2 h)	Sevoflurane vs. Propofol	Cognition: Lower early MMSE with sevoflurane; decline at 9-month follow-up Inflammation: Markers not correlated with cognition	Sevoflurane negatively impacts early and late cognitive state
Qiao Y et al. (2015) [86]	RCT	Elderly, major surgery	Sevoflurane vs. Propofol	Cognition: Lower MMSE/MoCA scores (POD 1,3,7) Inflammation: Higher TNF-α, IL-6, S-100β levels	Sevoflurane linked to higher POCD incidence with increased inflammation
Garg V et al. (2025) [87]	RCT	Adults, CABG	Sevoflurane vs. Propofol-TIVA	Cognition: Higher MMSE scores with TIVA (24 h/48 h) Inflammation: Comparable IL-6 response	TIVA may offer superior early cognitive recovery after cardiac surgery
Tachibana S et al. (2015) [88]	Pilot RCT	Elderly, long surgery (> 4 h)	Sevoflurane (1.0%) vs. Desflurane (3.5%)	Cognition: Improved MMSE with desflurane post-op	Desflurane may be associated with better cognitive recovery for lengthy procedures

CABG coronary artery bypass grafting, CNS central nervous system, MMSE mini-mental state examination, MoCA Montreal cognitive assessment, RCT randomized controlled trial, TIVA total intravenous anesthesia

This association is most consistently evident in elderly patients undergoing major surgery. In these populations, sevoflurane anesthesia has been associated with lower early postoperative cognitive scores when compared with intravenous propofol regimens [85, 86]. The observed cognitive impairment correlates with elevated plasma levels of pro-inflammatory cytokines and markers of neuronal injury. Thereby clinical observations align with preclinical hypotheses regarding neuroinflammation [86, 87].

The clinical impact of sevoflurane appears to be modulated by crucial perioperative variables. Evidence indicates that surgery magnitude influences cognitive outcomes and inflammatory profiles, with differences observed between major non-cardiac and cardiac procedures. Comparative studies among volatile anesthetics remain limited, yet emerging data suggest that anesthetic selection, particularly for prolonged procedures, may influence cognitive recovery in older adults [85, 86, 88]. These clinical findings suggest that the cognitive sequelae of sevoflurane are shaped by both patient susceptibility and procedural context.

Collectively, these clinical observations align with preclinical findings and point to several contextual determinants. Direct measurement of NLRP3 in patients is currently not feasible. Nonetheless, the association between sevoflurane and cognitive decline is most apparent under conditions that, in preclinical models, correspond to robust NLRP3 activation. These conditions include prolonged or high-dose exposures that may disrupt cellular homeostasis and elevate stress signals such as ROS, as well as major surgical procedures that provide a potent systemic inflammatory priming background through DAMPs and cytokines. This alignment raises the possibility that the combined burden of anesthetic exposure and surgical stress may influence the threshold and magnitude of the NLRP3-mediated neuroinflammatory response.

The Context-Dependent Neuroprotective Effects of Sevoflurane in Neurological Disorders

In contrast to its neurotoxic effects in aging, neurodegenerative predisposition, or prolonged exposure, sevoflurane exhibits neuroprotection properties under specific pathological conditions. This context-dependent duality reflects the interplay between anesthetic exposure and the cellular stress landscape. NLRP3 activation is consistently observed in models of AD and POCD, whereas suppression of the same pathway is reproducibly shown in acute injury models such as cerebral ischemia and neuropathic pain. This pattern indicates that the direction of NLRP3 modulation depends on the model context rather than being an intrinsic property of sevoflurane.

Cerebral ischemia–reperfusion injury occurs when blood flow is restored after ischemia, which leads to elevated ROS levels and NLRP3 inflammasomes activation [89]. In a rat model of middle cerebral artery occlusion, sevoflurane preconditioning improves neurological scores, reduces infarct volume [5]. Behavioral endpoints include shorter escape latency and more platform crossings in the water maze relative to untreated ischemic rats [5]. Structural endpoints comprise suppression of NLRP3, caspase 1, and IL-1β upregulation. The NLRP3 agonist nigericin reverses these effects, confirming pathway causality [5]. In other injury models, sevoflurane postconditioning has been reported to alleviate cognitive deficits by activating SIRT1 and promoting autophagy, which may reduce neuronal apoptosis [90]. Whether sevoflurane modulates NLRP3 directly or indirectly in these settings remains unclear, as does the question of how different administration timings engage distinct pathways such as SIRT1.

In rat hippocampal neurons subjected to oxygen-glucose deprivation (OGD), sevoflurane postconditioning upregulates Mafb and DUSP14 [21]. Structural endpoints show decreased levels of cleaved caspase‑1 and GSDMD, indicating reduced pyroptosis [21]. In vivo validation remains needed.

In a mouse model of neuropathic pain induced by chronic constriction injury, sevoflurane raises paw withdrawal mechanical threshold and prolongs paw withdrawal thermal latency from day five after surgery [4]. These behavioral endpoints indicate pain relief. Accompanying structural endpoints include reduced phosphorylation of PLCγ, CaMKII, and IP3R, lower ER stress markers, oxidative stress markers, and decreased NLRP3 and IL‑1β in the spinal cord [4].

In a cecal ligation and puncture model of sepsis-associated encephalopathy, sevoflurane improves cognitive function as measured by the Morris water maze [22]. Structural endpoints in the hippocampus comprise upregulation of SIRT1, restoration of TXN/TXNIP redox balance, inhibition of TLR4–TRIF signaling, and reduction of NLRP3, cleaved caspase‑1/11, GSDMD, IL‑1β, and IL‑18 [22].

Across diverse models of neurological disorders, sevoflurane exerts protective effects through distinct upstream mechanisms that converge on the suppression of NLRP3 mediated pyroptosis and neuroinflammation. Whether sevoflurane activates or suppresses NLRP3 is determined by the cellular stress profile, including SIRT1, ROS threshold, and autophagic competence. This molecular decision is reliably mirrored at the functional level. When the host milieu favors NLRP3 activation, as in advanced age or neurodegeneration, the neurotoxic phenotype manifests as impaired hippocampus dependent learning and memory, synaptic protein loss, and reduced dendritic spine density. When the same pathway is restrained under conditions of acute metabolic or ischemic stress, neuroprotection is characterized by preserved cognitive performance, reduced infarct volume, and retention of synaptic architecture. These divergent functional outcomes underscore a principle with direct translational relevance. The clinical impact of anesthetic exposure cannot be extrapolated from molecular pathway modulation alone. Instead, neurological outcome ultimately depends on whether the cellular context favors NLRP3 activation or suppression. Clarifying these molecular regulatory switches is critical for developing context-dependent neuroprotective strategies in clinical anesthesia. The bidirectional modulation of NLRP3 by sevoflurane and its context-dependent neurological effects are summarized in Fig. 3.

Fig. 3.

Bidirectional modulation of the NLRP3 inflammasome by sevoflurane determines neurotoxicity versus neuroprotection. Sevoflurane exerts context dependent dual effects on neurological outcomes with the NLRP3 inflammasome serving as the central signaling integrator. Under vulnerable conditions including aging AD and POCD, sevoflurane promotes NLRP3 inflammasome activation through upstream triggers such as ROS overproduction mitochondrial dysfunction impaired autophagy and disrupted ion homeostasis. This leads to caspase 1 mediated maturation of IL-1β and IL-18 and gasdermin D dependent pyroptosis culminating in cognitive impairment and synaptic injury. Conversely under acute pathological states such as cerebral IRI neuropathic pain and sepsis associated encephalopathy sevoflurane suppresses NLRP3 inflammasome assembly. This inhibition is mediated by the engagement of protective pathways including SIRT1 upregulation restoration of autophagic flux and preservation of intracellular calcium homeostasis. The resultant attenuation of neuroinflammation and pyroptosis confers structural and functional neuroprotection. The direction of NLRP3 modulation is ultimately dictated by the interplay between anesthetic exposure parameters and the prevailing cellular stress landscape. Abbreviations: AD, Alzheimer’s disease; IRI, ischemia reperfusion injury; NLRP3, NOD like receptor family pyrin domain containing 3; POCD, postoperative cognitive dysfunction; ROS, reactive oxygen species; SIRT1, sirtuin 1

NLRP3 Inhibitors: Types, Mechanisms, and Preclinical Evidence in Sevoflurane-Related Neurotoxicity

Because the NLRP3 inflammasome is implicated in sevoflurane-induced neuroinflammation and pyroptosis, pharmacological inhibition of this pathway has attracted interest as a promising therapeutic strategy. This section summarizes current knowledge on the principal classes of NLRP3 inhibitors, their mechanisms of action, and the supporting preclinical evidence, as presented in Table 2. All findings discussed herein derive exclusively from preclinical models. None of the NLRP3 inhibitors described have been approved for the prevention or treatment of sevoflurane-related neurotoxicity in clinical practice.

Table 2.

Summary of pharmacologic and interventional strategies targeting NLRP3-related neuroinflammation in sevoflurane-induced neurotoxicity

Therapeutic strategy	Compound	Target	Key findings
Inhibition of NLRP3 inflammasome assembly	MCC950 [58–60]	NLRP3 NACHT domain (ATPase activity)	Inhibits inflammasome assembly; Improves spatial memory in aged POCD mice; Hepatotoxicity concerns
	CY-09 [61, 62]	NLRP3 (ATP-competitive)	Anti-inflammatory in AD models
	P5091, HBX19818 [7, 63]	UAF1/USP7 deubiquitinase	Regulates NLRP3 ubiquitination status, inhibits inflammasome assembly and IL-1β release
Regulate upstream signaling pathways	Dexmedetomidine [51]	P2X4 receptor	Indirectly downregulates NLRP3; Reduces ROS and inflammasome activation
	TWS119 [46]	GSK3β	Synergistic with SB202190 to reduce hippocampal inflammation
	SB202190 [46]	P38 MAPK	Synergistic with TWS119 to reduce hippocampal inflammation
	RU5.21 [29]	cGAS-STING pathway	Blocks microglial cGAS-STING signaling; Inhibits NLRP3 activation
	NAC [29, 54]	ROS scavenger	Restores GSH homeostasis; Blocks NLRP3 activation
	Luteolin [65]	ROS, MDA, SOD	Improves learning and memory deficits in mice
	Cyclosporine A [29]	mPTP/VDAC inhibitors Mitochondrial function	Prevent ROS production and NLRP3 activation in microglia
	Honokiol [78]	PINK1/Parkin pathway	Enhances mitophagy; Reduces mtROS-NLRP3 axis activation
	ChIV [58]	ROS reduction	Alleviates oxidative stress; Indirectly reduces NLRP3 activation
	MitoQ [66]	Mitochondrial dynamics (Mfn1/2, Drp1/Fis1); Autophagy (LC3, p62)	Attenuates sevoflurane-induced cognitive decline; Improves mitochondrial function; Suppresses excessive autophagy and NLRP3 activation
	SESN2 [102]	Nrf2 pathway	Endogenous antioxidant; mitigates oxidative damage and NLRP3 activation
	miR-423-3p inhibitor [80]	GPX4	Down-regulation of miR-423-3p improves cognitive performance; Attenuates oxidative stress and neuroinflammation via GPX4 upregulation
	PAP-1 [72]	Kv1.3 channel	Attenuates cognitive impairment and neuronal damage; Inhibits microglial polarization and activation; Promotes M1-to-M2 shift via NLRP3 suppression
	Rapamycin [39, 60]	Autophagy activation	Clears damaged mitochondria; Synergistic with MCC950
Intervention of downstream pyroptosis and inflammatory effects	VX-765, Ac-YVAD-cmk [9, 54, 64]	Caspase-1	Block GSDMD cleavage and IL-1β release; Poor BBB penetration
	NSA [60]	GSDMD (Cys191)	Inhibits pore formation; May interfere with normal cell death
Systemic or Indirect Mechanisms	Apoptozole [74]	Hsc70/Hsp70 ATPase	Induces apoptosis; HDAC6 promotes POCD via HSP90/HSP70 in microglia
	Probiotics [71] Akkermansia muciniphila-EVs [84]	Gut-brain axis; Intestinal barrier (ZO-1, occludin)	Restores homeostasis; Reduces enterogenic LPS entry into brain; Improves cognitive function via gut barrier restoration and systemic inflammation reduction

AD Alzheimer’s disease, BBB blood-brain barrier, cGAS cyclic GMP-AMP synthase, ChIV Chikusetsu saponin Iva, GSH glutathione, GSDMD gasdermin D, GSK3β glycogen synthase kinase 3 beta, HO-1 heme oxygenase-1, IL-1β interleukin-1 beta, LPS lipopolysaccharide, MAPK mitogen-activated protein kinase, MDA malondialdehyde, mPTP mitochondrial permeability transition pore, mtROS mitochondrial reactive oxygen species, NAC N-acetylcysteine, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3, NACHT, LRR and PYD Domains-Containing Protein 3; Nrf2 nuclear factor erythroid 2-related factor 2, POCD postoperative cognitive dysfunction, ROS reactive oxygen species, SOD superoxide dismutase, STING stimulator of interferon genes, USP ubiquitin-specific peptidase, VDAC voltage-dependent anion channel

Classification and Mechanisms of Action

The most direct approach uses of compounds that bind to NLRP3 and inhibit its oligomerization and inflammasome assembly. These direct NLRP3 inhibitors include MCC950, which binds to the NACHT domain of NLRP3, suppressing its ATPase activity, and blocking inflammasome formation [58, 59]. Other strategies modulate the post-translational state of NLRP3. For example, the deubiquitinase inhibitor P5091 prevents NLRP3 deubiquitination and thereby suppresses inflammasome activation [63].

An alternative strategy targets key signaling pathways upstream of NLRP3 activation, before triggering signals reach the inflammasome. This approach includes the p38 MAPK/GSK3β axis, which is implicated in cellular priming and activation following anesthetic exposure and surgical trauma. Inhibitors like SB202190 and TWS119 can attenuate these upstream signals and may reduce NLRP3 activation [46]. Similarly, the cGAS-STING pathway translates sevoflurane-induced mtDNA release into an inflammatory signal and can be blocked by compounds such as RU.521 to provide an upstream checkpoint against NLRP3 engagement [29].

Downstream intervention targets the terminal inflammatory and pyroptotic executors of the NLRP3 pathway. These agents aim to control inflammatory after inflammasome assembly. Caspase-1 inhibitors such as VX-765 and Ac-YVAD-cmk, prevent the cleavage and maturation of pro-inflammatory cytokines IL-1β and IL-18. They also block GSDMD cleavage, a critical step in pyroptotic pore formation [9, 64]. Another downstream strategy directly targets GSDMD with inhibitors such as necrosulfonamide. This compound prevents GSDMD pore oligomerization in the plasma membrane and halts pyroptotic cell death independently of caspase inhibition [60].

Finally, a broad group of indirect modulators and multi-target agents may confer neuroprotection by influencing upstream cellular processes that converge on NLRP3 activation. This category includes natural compounds and repurposed drugs that restore cellular homeostasis. For instance, antioxidants such as N-acetylcysteine scavenge ROS, a potent NLRP3 trigger [29]. Autophagy inducers such as rapamycin promote mitophagy, which removes damaged mitochondria that would otherwise activate NLRP3 [39]. Modulators of the gut-brain axis, including probiotics such as Akkermansia, may reduce systemic inflammatory tone and the priming of central immune cells [71].

Summary of Preclinical Efficacy

As shown in Table 2, multiple inhibitors have shown beneficial effects against sevoflurane-induced cognitive impairments and neuropathological changes in animal models. MCC950 and caspase-1 inhibitors can reduce hippocampal IL-1β levels, attenuate neuronal pyroptosis, and improve performance in spatial memory tasks in aged or surgically stressed mice exposed to sevoflurane [58, 60, 64]. Inhibitors targeting upstream signaling pathways such as p38 MAPK or cGAS-STING not only suppress NLRP3 activation but also ameliorate associated pathologies including tau hyperphosphorylation and microglial activation [29, 46]. Indirect strategies, such as the autophagy enhancer honokiol and the antioxidant luteolin, may restore cellular homeostasis and thereby limit NLRP3 activation [65, 78].

The Translational Gap: From Bench to Bedside

Preclinical studies have validated NLRP3 inflammasome inhibition as a potential strategy to alleviate sevoflurane-induced neurotoxicity. However, this approach has yet to be reach clinical application, largely owing to pharmacological and safety challenges associated with current inhibitors.

A primary translational challenge is achieving sufficient molecular specificity to limit adverse events. Several candidate compounds, though effective in preclinical models, exhibit off-target activity beyond NLRP3. For instance, the widely studies inhibitor MCC950 has been associated with potential hepatotoxicity and interactions with cardiac potassium channels [39]. These observations highlight the need for next-generation analogs with improved selectivity to a broader therapeutic window.

Another major barrier is the unfavorable pharmacokinetic profile of many inhibitors, particularly their limited ability to cross the BBB. Modulating neuroinflammation effectively requires adequate drug exposure within the CNS. Several promising agents, including certain caspase-1 inhibitors, show poor brain bioavailability after systemic administration [9]. This restricted CNS penetration limits their utility for perioperative neurocognitive disorders. Novel delivery systems or chemical modifications that enhance BBB permeability therefore merit further exploration.

Alternative administration routes that bypass the BBB have been examined. Intrathecal delivery of the MCC950 effectively reduced allodynia in a rat model of neuropathic pain [91]. The caspase-1 inhibitors Ac-YVAD-cmk and VX-765 have been administered via intracerebroventricular injection to confer neuroprotection in a cerebral ischemia model [92, 93]. Although these invasive approaches provide proof-of-principle, their routine perioperative use remains impractical. This limitation highlights the need for brain-penetrant inhibitors such as the oral NLRP3 inhibitor NT-0796 in subjects with Parkinson’s disease [94].

Comprehensive long-term toxicity evaluation remains limited in current developmental pipelines. These efforts must balance immunosuppression with preservation of essential host immunity. Preclinical studies often prioritize efficacy over exhaustive toxicological profiling. A key concern is the risk of excessive NLRP3 inflammasome suppression, given its vital role in innate immune defense [34, 40]. Identifying a dosing regimen that attenuates pathological neuroinflammation without increasing infection susceptibility therefore remains an unresolved safety challenge.

In summary, the preclinical proof-of-concept for NLRP3 inhibition is well established. Clinical translation will require overcoming limitations in drug specificity, CNS delivery, and systemic safety. The following section expands on these challenges and outlines research directions that may help bridge the gap between preclinical findings and clinical application.

Future Directions

Collectively, available evidence suggests that the NLRP3 inflammasome is an important determinant of the context-dependent neurological effects of sevoflurane. Nevertheless, translating this mechanistic understanding into clinical practice faces fundamental challenges. Current research remains fragmented and largely correlative. The field is characterized by substantial model heterogeneity, including diverse cell types, animal ages, and injury paradigms. Standardized and causally defined exposure thresholds that reliably distinguish neurotoxicity from neuroprotection are lacking. Although animal models are indispensable for discovery, they offer preclinical proof-of-concept. The clinical reality of POCD or neuroprotection in patients involves far more complex and comorbid physiological conditions than current models can fully recapitulate. This disparity creates a considerable translational gap.

To address these limitations, future investigations should advance along three strategic fronts. First, emphasis should shift from describing bidirectional effects to identifying the decisive molecular switches. Studies should prioritize the characterization of specific cellular states or signaling nodes, such as metabolic profiles and distinct combinations of DAMPs, that determine whether sevoflurane activates or inhibits NLRP3 in a given context. This shift moves the field from establishing associations toward elucidating causal mechanisms [50, 60, 95, 96]. Second, therapeutic development should adopt context-dependent and combinatorial strategies. Given the complexity of the pathway, a universal inhibitor appears unlikely to succeed. Research should instead explore approaches that combine precise anesthetic dosing with adjunctive and targeted modulation of NLRP3, tailored to the patient’s perioperative inflammatory status. Ultra-low dose sevoflurane regimens may represent one such avenue [16–18]. third, the translational pipeline requires more sophisticated modeling. This includes validating mechanisms in aged or disease progressive animal models that better reflect vulnerable patient populations and developing clinically applicable biomarkers that report NLRP3 activity to enable patient stratification.

Whether the NLRP3 inflammasome functions as a shared signaling node for other anesthetic agents also warrants brief consideration. Isoflurane exhibits a similar dichotomy. It activates NLRP3 to induce cognitive impairment in aged animals yet suppressing the TLR4-NLRP3 axis to confer protection in diabetic stroke models [97–99]. Propofol promoting NLRP3 mediated developmental neurotoxicity while inhibiting inflammasome signaling in ischemic injury [100, 101]. This pattern suggests that context driven NLRP3 modulation may be a common feature across diverse anesthetic classes, although comparative studies remain limited.

The ultimate objective is to leverage this comprehensive NLRP3 framework to inform precision anesthesiology. Such an approach would guide risk assessment, refine anesthetic protocols, and personalize adjuvant therapies to optimize neurological outcomes.

Conclusion

This review positions the NLRP3 inflammasome as a critical integrator of sevoflurane’s bidirectional neurological effects. Under vulnerable conditions such as aging or neurodegeneration, sevoflurane engages NLRP3-driven pyroptosis and neuroinflammation to promote neurotoxicity. Under acute metabolic or ischemic stress, it can suppress this same pathway and exert protection. The net outcome reflects the interplay between exposure parameters and the host cellular stress landscape. Preclinical findings are compelling, yet translation remains constrained by model heterogeneity, correlative data, and undefined exposure thresholds. Advancing precision anesthesiology will require identifying the molecular switches that dictate NLRP3 activation versus inhibition, developing context-dependent therapeutic strategies, and validating biomarkers in clinically relevant models.

Abbreviations

NLRP3

NOD-like receptor family pyrin domain containing 3

AD

Alzheimer’s disease

CNS

Central nervous system

PD

Parkinson’s disease

POCD

Postoperative cognitive dysfunction

PYD

Pyrin domain

CARD

Caspase recruitment domain

ASC

Apoptosis-associated speck-like protein containing a CARD

NACHT

Nucleotide-binding and oligomerization domain containing

GSDMD

Gasdermin D

TLR

Toll-like receptor

DAMPs

Damage-associated molecular patterns

ROS

Reactive oxygen species

PAMPs

Pathogen-associated molecular patterns

LPS

Lipopolysaccharide

TXNIP

Thioredoxin-interacting protein

PRDX3

Peroxiredoxin-3

HMGB1

High mobility group box 1

BDNF

Brain-derived neurotrophic factor

BBB

Blood-brain barrier

OGD

Oxygen-glucose deprivation

Author Contribution

Gang Chen: Conceptualization, Methodology, Supervision. Nuan Li: Data curation, Writing- Original draft preparation. Yeru Chen: Writing- Reviewing and Editing.

Funding

This research was supported by the National Natural Science Foundation of China (No.82371185).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval and Consent to Participate

Not applicable.

Competing Interests

The authors declare no competing interests.

Consent for Publication

All authors agreed to publish this study.