Modulation of ER Stress and Inflammation by S-Ketamine, R-Ketamine, and Their Metabolites in Human Microglial Cells: Insights into Novel Targets for Depression Therapy.
Cells June 3, 2025 Marta Jóźwiak-Bębenista, Anna Wiktorowska-Owczarek, Małgorzata Siatkowska et al. 4 citations
Ketamine and its metabolites—including R-ketamine, S-ketamine, and the hydroxynorketamines (2S,6S-HNK and 2R,6R-HNK)—directly reduce markers of endoplasmic reticulum (ER) stress and inflammation in human microglial cells. In cells treated with tunicamycin to induce ER stress, all compounds lowered expression and protein levels of CHOP and GRP78, two key components of the unfolded protein response (UPR). In microglia stimulated with lipopolysaccharide (LPS), the compounds decreased levels of the inflammatory cytokine IL-6 and, to a lesser extent, IL-8. These findings point to a glia-targeted mechanism for modulating ER stress and neuroinflammation, supporting further in vivo research to develop antidepressants with fewer psychoactive side effects than current treatments.