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

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.