Mol Neurobiol. 2025 Nov 11;63(1):25. doi: 10.1007/s12035-025-05344-z.
ABSTRACT
Seizures are common in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, yet the mechanisms beyond antibody-mediated NMDAR hypofunction remain poorly understood. This study investigated whether microglial NLRP3 inflammasome activation increases seizure susceptibility and whether its inhibition confers protection. In a pediatric cohort of sixty patients, serum levels of NLRP3 and IL-1β were elevated in patients compared with controls. Multivariable models indicated that NLRP3 was independently associated with seizure presence, whereas IL-1β did not retain independent significance when modeled alongside NLRP3, and model discrimination improved modestly when both markers were included. In an active-immunization mouse model using the GluN1356-385 peptide, pentylenetetrazol exposure resulted in shorter seizure latency and increased severity, accompanied by cortical microglial activation and upregulation of the NLRP3-ASC-caspase-1-IL-1β pathway. Pharmacologic NLRP3 inhibition with MCC950 elevated seizure threshold and reduced seizure burden. Correspondingly, cortical c-Fos/NeuN staining revealed heightened neuronal activation in immunized mice, which was attenuated by MCC950. Notably, MCC950 did not reverse the decrease in membrane NMDAR levels, indicating seizure protection independent of NMDAR function recovery. These clinical and experimental results indicate that NLRP3 inflammasome contributes to lowered seizure threshold in anti-NMDAR encephalitis, operating downstream of or in parallel to NMDAR hypofunction. NLRP3 represents a potential serum biomarker for seizure risk and a promising adjunct therapeutic target, supporting further evaluation of inflammasome inhibition during acute disease stages.
PMID:41217696 | DOI:10.1007/s12035-025-05344-z
