Targeting NMDAR2A: Esketamine's Impact on BV2 Microglial Pro-inflammatory Polarization

The polarization of microglia to the pro-inflammatory phenotype plays a crucial role in the initiation and progression of neuroinflammatory diseases, primarily owing to the secretion of pro-inflammatory cytokines that exacerbate damage within the central nervous system (CNS). Investigating the mechanisms underlying the inhibition of microglial pro-inflammatory polarization could be the potential targets for the prevention of neuroinflammatory diseases. The activation of N-methyl-D-aspartic acid (NMDA) receptors can mediate the over-activation and toxicity of microglia. Due to the unique structure of NMDA receptors, it has different subtypes and perform distinct functions. Our study indicates that Esketamine, a non-competitive antagonist of NMDAR, can up-regulate the phosphorylated Mammalian target of rapamycin (mTOR) and Brain-derived neurotrophic factor (BDNF)-Tropomyosin-related kinase receptor B (TrkB) signaling pathway by inhibiting the 2A subtype of NMDA receptors, attenuates LPS-induced pro-inflammatory polarization of BV2 microglia and reduces the expression of pro-inflammatory cytokines. However, the NMDAR2B subtype does not appear to be involved in this process.