Efeito imunomodulador e sinaptogênico dos enantiômeros R- e S-cetamina no modelo inflamatório de depressão induzido por lipopolissacarídeo

Abstract

Depression is a disabling mental disorder associated with increased levels of pro-inflammatory cytokines and glial activation. Ketamine has emerged as a modifying agent in the psychopharmacology of depression, as it exerts effect in hours with high responsiveness. This drug, however, consists of a racemic mixture of the R- and S-ketamine enantiomers (R- and S-KET) that have different behavioral effects and molecular targets. This study aims to investigate the immunomodulatory and synaptogenic profile of R- and S-KET in the model of depression induced by the lipopolysaccharide (LPS) administration. To do this, male Wistar rats were challenged with LPS (0.83 mg / kg, ip.). After 24 hours, the animals received R-KET or S-KET (10 mg / kg, ip.), and 2 hours later, they were evaluated for depressive-like behaviors and adverse psychomimetic effects. At the end, the animals were sacrificed and brain samples of the hippocampus and serum were collected. In addition, BV2 microglial cultures were challenged with LPS (100 ng / ml) for 24 hours and 2 hours later were exposed to R- or S-KET. Both enantiomers reversed some depressive-like behaviors induced by LPS, as well as the reactive increase in serum corticosterone. LPS caused intense glial activation, demonstrated by markers of microglial (Iba1) and astrocytic (GFAP) reactivity in the hippocampus. This was accompanied by an increase in nitrite, proinflammatory cytokines TNFα and IL-6 and M1 phenotype markers (iNOS and CD86 mRNA). Both enantiomers attenuated the increase in Iba1 and GFAP in the hippocampus, but only S-KET induced an M2 phenotype, indicated by the increase in the arginase activity, cytokines IL-4 and IL-10 and the expression of M2a response genes (LGLAS3 and IGF-1). In the BV2 cells, S-KET increased arginase activity and IL-4 and IL-10 levels, which was compatible with the M2 profile. Both R- and S-KET reversed the LPS-induced changes in synaptic ultrastructure and isolated synaptosomes. However, only S-KET increased the density and the presence of mature synaptic forms in the dentate gyrus. Also, S-KET increased BDNF expression and maturation rate in the hippocampus, as well as increased this neurotrophin secretion by BV2 microglia. Therefore, the present study demonstrated, for the first time, the superior immunomodulatory profile of S-KET, being able to promote a reparative M2 phenotype and protect synaptic structures from the damage associated with the immune challenge. In the end, our results contribute to the understanding of the mechanisms underlying the antidepressant effect of ketamine, as well as to the preferential repurposing of S-KET to chronic inflammatory conditions.