Kynurenic acid (KYNA) is implicated in antiinflammatory processes in the brain through several cellular and molecular targets, among which microglia-related mechanisms are of paramount importance. In this study, we describe the effects of KYNA and one of its analogs, the brain-penetrable SZR104 (N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide), on the intracellular distribution and methylation patterns of
histone H3 in immunochallenged microglia cultures. Microglia-enriched secondary cultures made from newborn rat forebrains were immunochallenged with
lipopolysaccharide (LPS). The
protein levels of selected inflammatory markers C-X-C motif
chemokine ligand 10 (CXCL10) and C-C motif
chemokine receptor 1 (CCR1),
histone H3, and posttranslational modifications of
histone H3 lys methylation sites (H3K9me3 and H3K36me2, marks typically associated with opposite effects on gene expression) were analyzed using quantitative fluorescent immunocytochemistry and western blots in control or LPS-treated cultures with or without KYNA or SZR104. KYNA and SZR104 reduced levels of the inflammatory marker
proteins CXCL10 and CCR1 after LPS-treatment. Moreover, KYNA and SZR104 favorably affected
histone methylation patterns as H3K9me3 and H3K36me2 immunoreactivities, and
histone H3 protein levels returned toward control values after LPS treatment. The cytoplasmic translocation of H3K9me3 from the nucleus indicated inflammatory distress, a process that could be inhibited by KYNA and SZR104. Thus, KYNA signaling and metabolism, and especially brain-penetrable KYNA analogs such as SZR104, could be key targets in the pathway that connects
chromatin structure and epigenetic mechanisms with functional consequences that affect
neuroinflammation and perhaps neurodegeneration.