Sex-specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression

•Seven-day LPS treatment evoked depressive behavior in both sexes.•The treatment decreased levels of mitochondrial GR and pGR232/pGR246 ratio only in females.•Alterations in GR detected in hippocampus of females were followed by decreased mRNA levels of COX-1 and COX-3.•Decreased levels of COX-1 and COX-3 mRNA could indicate impaired oxidative metabolism in hippocampus of females.•Changes in GR and BCL-2 family members in hippocampus of females could protect these cells from LPS-induced apoptosis. Mitochondria play a significant role in pathogenesis of clinical depression and their function can be impaired by inflammation and alterations in hypothalamic–pituitary–adrenal axis. Sexual context is also a relevant factor in the incidence of mood disorders, and could have a strong influence during an immune challenge. Therefore, in this study we investigated whether the effects of seven-day lipopolysaccharide (LPS) treatment on glucocorticoid receptor (GR) could be associated with apoptosis and alterations in energy metabolism in hippocampus of female and male Wistar rats with depressive-like behavior. To that end, we measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246 in hippocampus of female and male rats, as well as the mRNA levels of two GR-regulated mitochondrial genes, cyclooxygenase -1 and -3 (COX-1 and -3). We also measured alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of hippocampus of these animals, and the levels of cleaved cytosolic poly [ADP-ribose] polymerase-1 (PARP-1) protein. We discovered that even though LPS treatment induced behavioral alterations and affected corticosterone levels and apoptosis in a similar manner in both sexes, it affected mitochondrial GR differently in males and females. Namely, the treatment decreased levels of mitochondrial GR and pGR232/pGR246 ratio only in females, and these alterations were followed by decreased mRNA levels of COX-1 and COX-3 only in this sex. The alterations in COX-1 and COX-3 mRNA levels could indicate impaired oxidative metabolism and diminished mitochondrial function in hippocampus of this sex.