R- and S-ketamine abrogate lipopolysaccharide-induced depressive-like behavior through microglial modulation: a differential anti-inflammatory and neurotrophic effect of the enantiomers

Abstract

Abstract Depression is a mental disorder associated with increased proinflammatory cytokines and glial activation. Ketamine (KET), a racemic mixture of the R- and S-KET enantiomers, emerged as a rapid antidepressant drug. This study aimed to investigate the microglial modulatory and synaptogenic effects of R- and S-KET in a lipopolysaccharide (LPS)-induced depression model. Male rats were challenged with LPS and, 24h later, received R-KET or S-KET (10 mg/kg, IP). Two h later, these animals were evaluated for depression-like behaviors and adverse psychomimetic effects. Also, BV2 microglial cultures were challenged with LPS and exposed to R- or S-KET. Both enantiomers reversed LPS-induced depression-like behaviors and increased plasma corticosterone. LPS caused intense hippocampal glial activation, demonstrated by microglial (Iba1) and astrocytic (GFAP) markers, accompanied by increased nitrite, pro-inflammatory cytokines TNFα and IL-6, and M1 microglial phenotype markers (iNOS and CD86 mRNA). Both enantiomers attenuated Iba1 and GFAP hippocampal increase, but only S-KET induced an M2 phenotype, indicated by the higher arginase activity, IL-4, IL-10, and expression of M2a response genes (LGLAS3 and IGF-1). In the BV2 cells, S-KET increased arginase activity, IL-4, and IL-10 levels. Both enantiomers reversed the LPS-induced changes in synaptic ultrastructure and synaptosome viability, while only S-KET increased the density and the presence of mature spines in the dentate gyrus. Also, S-KET increased hippocampal BDNF maturation and boosted its secretion by BV2 microglia. Therefore, the present study demonstrated, for the first time, the unique immunomodulatory profile of S-KET, promoting a reparative M2 phenotype and protecting synaptic structures from the LPS-associated damage.