Review links sevoflurane exposure during development to neuroinflammatory pathways linked with neurotoxicity

A mini review concludes that neuroinflammation is an important potential mechanism through which sevoflurane exposure during development may contribute to neurotoxicity. The review synthesizes animal, cell and human evidence, with the strongest mechanistic findings coming from preclinical models of repeated or prolonged exposure. Human studies remain limited and inconsistent, so the reviewed evidence does not establish that a single clinical exposure causes lasting neurological harm.

Sevoflurane is a commonly used inhalational anaesthetic, particularly in paediatric care. Its blood-gas solubility is 0.69, compared with 0.42 for desflurane, and the review says this contributes to rapid induction and recovery. A five-compartment mammillary model describes the absorption, distribution and disposal of volatile anaesthetics. After anaesthesia is discontinued, sevoflurane is eliminated faster than isoflurane and halothane, with only desflurane and nitrous oxide ranked as faster in the review.

Animal studies provide the clearest warning signals for developmental neurotoxicity. Maternal sevoflurane anaesthesia in mice has been associated with impaired social interaction in offspring, while neonatal exposure has been linked to cognitive impairment in adulthood. Repeated prenatal exposure in mice produced attention-deficit/hyperactivity disorder-like impulsive behaviour later in adulthood. In monkeys, infant exposure produced greater anxiety-related behaviour during adolescence, and recurrent exposure early in infancy was associated with an anxious phenotype that continued to develop over time. These observations demonstrate neurological outcomes in animal models rather than clinical benefits or quantified risks in children.

The reviewed preclinical evidence indicates that exposure pattern may matter. A single brief exposure generally caused only transient and modest changes in dendritic-spine density and neuronal function in experimental paradigms, without appreciable long-term behavioural effects. By comparison, repeated or extended exposure was associated with blocked hippocampal long-term potentiation, heightened neuroinflammatory activation and deficits in learning and memory. Tau phosphorylation after prolonged, multi-day exposure was strongly associated with cognitive impairment in experimental datasets, while brief exposure elicited only modest neurobehavioural effects. Persistent changes in dendritic arborization were also reported into adolescence after a single postnatal-day-7 exposure in rats.

Microglial activation is central to the proposed pathway. Microglia are resident immune cells of the central nervous system and account for 10%–15% of all glial cells, according to the review. At baseline, they support neighbouring cells with nutrients, regulate neuronal growth and sample their surroundings. Following injury or other activating conditions, they can release reactive oxygen species, nitric oxide and inflammatory mediators. Repeated sevoflurane exposure in newborn mice activated microglia and increased TNF-α, IL-8, IL-6 and IL-1β. Sevoflurane exposure in rapidly developing monkey brains was also associated with increased microglial activation, detected through greater translocator-protein expression.

Several signalling routes connect sevoflurane exposure to this inflammatory response. The review describes increased release of the endogenous danger signals HMGB-1 and galectin-3 in hippocampal tissue, followed by activation of microglial TLR4 and TLR9, the MyD88-dependent pathway and PI3K/AKT signalling. Increased IκBα phosphorylation and NF-κB transcription accompany greater production of TNF-α, IL-1β and IL-6. Notch, Toll-like, AMPK and PI3K/AKT/mTOR pathways were also implicated. The effect is context-dependent: in sepsis models, sevoflurane suppressed TLR4 activation and NF-κB signalling, indicating that its inflammatory effects can differ by species and underlying condition.

The cholinergic anti-inflammatory system may also be affected. The α7 nicotinic acetylcholine receptor normally limits NF-κB nuclear translocation in macrophages and activates the JAK2–STAT3 pathway, including expression of the anti-inflammatory factor IL-10. In rats, repeated therapeutic-dose sevoflurane exposure reduced hippocampal acetylcholinesterase expression, while reduced presynaptic acetylcholine release lowered α7 nicotinic acetylcholine receptor activity. The receptor agonist PNU-282987 counteracted the associated cognitive loss in rats, supporting involvement of this pathway in that animal model.

The review gives particular attention to NLRP3 inflammasome activation in microglia and neurons. Upstream events described include mitochondrial dysfunction, excessive reactive oxygen species, potassium efflux, calcium dysregulation and impaired autophagic clearance. Mitochondrial DNA leakage can activate the cGAS–STING axis, while the HDAC6–HSP90/HSP70 axis is reported to accelerate inflammasome assembly. NLRP3 activation leads to caspase-1-dependent cleavage of pro-IL-1β and pro-IL-18; gasdermin D drives pyroptotic cell death and can reinforce inflammation. Sevoflurane is also reported to inhibit histone lactylation at H3K18, reduce translation of the antioxidant enzyme PRDX3 and alter PER2 methylation, linking oxidative stress and epigenetic regulation to inflammasome activity.

Preclinical interventions have reduced some sevoflurane-associated outcomes by targeting these pathways. Insulin-like growth factor 1 restored sevoflurane-suppressed AKT phosphorylation in rats. In mice, deletion of the hippocampal inflammatory regulator TREM1 reduced pro-inflammatory microglial polarisation, neuroinflammation and cognitive impairment. Morroniside promoted an anti-inflammatory microglial phenotype and inhibited TLR4/NF-κB activation, reducing hippocampal damage and neuroinflammation in experimental models. Such findings identify therapeutic hypotheses, but they do not establish an effective clinical treatment for children.

Translation remains limited by incomplete long-term toxicity evidence, drug specificity, blood–brain barrier penetration and the need to preserve innate immunity. The NLRP3 inhibitor MCC950 has shown potential cardiac potassium-channel interactions and hepatotoxicity, while some candidate drugs have low brain bioavailability after systemic administration. Because NLRP3 has an important role in innate immune defence, excessive suppression may increase infection risk, and an effective dosing schedule remains unresolved. The review therefore supports further investigation of neuroinflammatory mechanisms while emphasizing that current evidence is predominantly preclinical, that human findings are contradictory and limited, and that no neuroprotective strategy has yet been clinically established.

Subject of Research: Preclinical evidence on neuroinflammatory mechanisms of sevoflurane-induced developmental neurotoxicity

Article Title: Neuroinflammation: an important mechanism of sevoflurane-induced developmental neurotoxicity

Article References: Liu, X., Zhou, Y., & Xiang, T. (2026). Neuroinflammation: an important mechanism of sevoflurane-induced developmental neurotoxicity. Frontiers in Pharmacology, 17, Article 1979399. https://doi.org/10.3389/fphar.2026.1979399

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1979399

Keywords: sevoflurane, developmental neurotoxicity, neuroinflammation, microglial activation, NLRP3 inflammasome, paediatric anaesthesia, cognitive impairment, preclinical research, important, mechanism, sevoflurane-induced, developmental