Neuropathological implication of high blood bilirubin in patients and model rats with depression

Elevated bilirubin levels have been associated with major depressive disorder (MDD); however, the exact impact of bilirubin on MDD and the underlying molecular mechanisms remain unclear. Here, we explored the influence of bilirubin on MDD and sought to identify the mechanisms via which bilirubin induces depressive-like behavior. Forty patients who were diagnosed with MDD and received treatment with selective serotonin reuptake inhibitors (SSRIs) were included, with 43 healthy volunteers serving as controls. Clinical symptoms were evaluated using Hamilton depression rating scale-24 (HAMD-24) and the Hamilton anxiety rating scale. Serum concentrations of total bilirubin (TBIL) and indirect bilirubin (IBIL) were measured at baseline and after treatment using an automated biochemical analyzer. The connection between clinical symptoms and TBIL or IBIL was examined using Pearson correlation. Chronic restraint stress (CRS) was employed to generate a rat model of depression. TBIL, IBIL in rat serum were measured by ELISA. Reactive oxygen species (ROS) contents in rat hippocampal tissues were quantified by flow cytometry. The levels of microglial markers and the extent of neuronal damage in the rat hippocampus were assessed by immunofluorescence and transmission electron microscopy, respectively. Serum TBIL and IBIL levels were higher in patients with MDD than in the healthy controls. After treatment with SSRIs, the serum levels of TBIL and IBIL in MDD patients were significantly reduced. The levels of TBIL and IBIL were associated with HAMD-24 in MDD patients. Compared with the controls, the serum levels of TBIL, IBIL and the hippocampal ROS contents were elevated in CRS-exposed rats. Fluoxetine lowered inflammatory factor levels, mitigated oxidative stress. Our findings indicate a possible correlation between elevated serum bilirubin and depressive symptoms. Increases in ROS levels, along with neuronal damage, may represent pathological mechanisms underlying MDD. •High doses of bilirubin can cause depression-like behavior in rats by inducing inflammation and damaging synaptic plasticity in the hippocampus.•Clinical and animal experiments are combined to ensure result accuracy.•Depression may be diagnosed by measuring bilirubin levels, indicating its potential as a biomarker for depressive activity.