Targeting NMDAR2A in microglia: esketamine suppresses M1 polarization in BV2 cells

Microglial polarization toward the M1 phenotype is a key contributor to the initiation and progression of neuroinflammatory diseases, primarily through the release of pro-inflammatory cytokines that exacerbate central nervous system-associated injury. Activation of N-methyl-D-aspartic acid receptors (NMDARs) is implicated in microglial overactivation and cytotoxicity. This study aimed to investigate the role of esketamine, a non-competitive NMDAR antagonist, on microglial polarization.

BV2 microglial cells were used as an in vitro model. Inhibitors and agonists were applied to modulate the mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signaling pathways. Small interfering RNA, Western blotting, enzyme-linked immunosorbent assay, and immunofluorescence staining were performed to investigate the regulatory effects and molecular targets of esketamine on BV2 cells.

Esketamine enhanced mTOR phosphorylation and activated the BDNF-TrkB signaling pathway through NMDAR inhibition. This effect attenuated lipopolysaccharide-induced M1 polarization in BV2 microglia and reduced pro-inflammatory cytokine expression. Further analysis revealed that the anti-inflammatory effects of esketamine were primarily mediated by the NMDAR2A subtype, while the NMDAR2B subtype was not involved.

Esketamine suppressed proinflammatory microglial polarization by selectively modulating the NMDAR2A subtype, leading to the activation of the mTOR signaling pathway and enhancement of the BDNF-TrkB signaling pathway.