Oseltamivir Phosphate Modulates CD24-Siglec-G/10 Interaction to Suppress Microglial-Driven Neuroinflammation After Cardiac Arrest

Abstract

Background

In cardiac arrest (CA) patients undergoing cardiopulmonary resuscitation (CPR), neuroinflammation following return of spontaneous circulation (ROSC) contributes to brain ischemia/reperfusion injury and neurological dysfunction. Recent evidence suggested that neuraminidase could exacerbate inflammatory responses by disrupting CD24-Siglec-G/10 immune checkpoint axis. As a neuraminidase inhibitor, oseltamivir phosphate (OP) holds potential for immunomodulation beyond its antiviral use. We aimed to investigate the impact and mechanism of OP on neuroinflammation regulation after ROSC.

Methods

Male pigs were randomized into the sham control group, CPR, and CPR + OP group. CA was induced in pigs through 8 min of untreated ventricular fibrillation. Brains were harvested for assessing serum inflammatory markers and neuronal damage at 24 h after ROSC. BV2 microglial underwent oxygen–glucose deprivation/reperfusion (OGD/R). Effects of OP on inflammatory responses, NF-κB activation, cell viability, and the CD24-Siglec-G/10 interaction were evaluated using immunofluorescence, immunoprecipitation, molecular, and biochemical assays.

Results

In vivo, OP attenuated pig cerebral microglial activation and neuronal integrity with attenuated neuroinflammation, alongside time-dependent neuraminidase activity increases. In vitro, OP suppressed OGD/R-induced microglial NF-κB activation, reduced pro-inflammatory cytokine levels, and preserved CD24-Siglec-G interaction, correlating with diminished neuraminidase release.

Conclusions

OP as a repurposed immunomodulator that suppresses microglial-driven neuroinflammation after CA by preserving sialylation-dependent CD24-Siglec-G/10 interaction.