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

  • CNS Neurosci Ther. 2025 Aug;31(8):e70495. doi: 10.1111/cns.70495.
Yushu Chen  1  2 ,  Ying Liu  2 ,  Na Li  3 ,  Ling Wang  4 ,  Peijuan Li  5 ,  Zhangping Sun  6 ,  Dongping Yu  7 ,  Ziren Tang  8 ,  Ping Gong  1
Affiliations
  • 1. Department of Emergency Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, School of Medicine, Southern University of Science and Technology), Shenzhen, Guangdong, China.
  • 2. Department of Emergency Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
  • 3. Department of General Medicine, Xinqiao Hospital, Army Medical University, Chongqing, China.
  • 4. Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
  • 5. Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 6. Department of Medical Intensive Care Unit (MICU), Zhongshan Hospital Affiliated to Dalian University, Dalian, Liaoning, China.
  • 7. Department of Emergency Medicine, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
  • 8. Department of Emergency Medicine, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, Liaoning, China.
PMID: 40836885 DOI: 10.1111/cns.70495
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.

Keywords
CD24; NF‐κB; SiglecG/10; cardiac arrest; microglia; neuroinflammation; oseltamivir; therapeutic targets.
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