Protective effects of estradiol on neuroinflammation in chronic obstructive pulmonary disease related depression

Depression among women with chronic obstructive pulmonary disease (COPD) has garnered significant attention. The role of estradiol (E2) on COPD-related depression is unknown. Therefore, this study aimed to investigate the role and underlying mechanism of E2 in COPD related depression.

Female and ovariectomized (OVX) Sprague-Dawley rats (SD rats) were exposed to cigarette smoke (CS) to establish a COPD model. At the end of the experiment, behavioral tests to assess behavioral alterations were tested, pulmonary functions were measured, lung and brain tissue were observed for pathological change. Additionally, we evaluated the levels of oxidative stress and inflammation-related proteins of brain tissue. In vitro, BV2 microglial cells stimulated with lipopolysaccharide (LPS) were treated with E2 to elucidate the molecular mechanisms by which E2 affects neuroinflammation.

COPD rats exhibited depression-like behavior, accompanied by a significant decrease in 5-hydroxytryptamine (5-HT) levels in the plasma and cerebral cortex. The combination of OVX and CS exposure resulted in a rat model of COPD-related depression. In this model, brain microglia and astrocytes were activated, with increased expression of nuclear factor erythroid 2-related factor-2 (Nrf2), quinone oxidoreductase 1 (NQO1), heme-oxygenase-1 (HO1), and phosphorylated nuclear factor kappa B (p-NFκB) proteins, alongside enhanced M1 polarization in microglia. These changes were correlated with the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK). In vitro, E2 significantly mitigated LPS-induced M1 polarization and inflammation via ERK1/2 and JNK pathways in BV2 microglial cells.

Our findings indicate that E2 protects against depression-like behavior induced by CS, which may be related to the activation of microglia and M1 polarization through the ERK1/2 and JNK pathways. Furthermore, estrogen levels appear to play a crucial role in the anti-neuroinflammatory processes associated with the onset and progression of depression in COPD.