Loganin Modulates Sigma‐1 Receptor to Alleviate Depression: Animal, Cellular, and Computational Evidence

Inflammation is known to exacerbate depressive symptoms. Loganin, a major iridoid glycoside derived from Cornus officinalis Sieb. et Zucc., exhibits antidepressant-like properties and anti-inflammatory effects; however, the mechanisms underlying these actions remain unclear. Given the involvement of the Sigma-1 receptor (Sigma-1R) in both depression and neuroinflammation, this study aimed to investigate whether loganin can ameliorate inflammation-related depression by modulating Sigma-1R. Experimental models of social isolation and lipopolysaccharide (LPS)-induced depressive-like behaviors were employed. The effects of loganin on behavioral outcomes, neurons, astrocytes, and microglia, oxidative stress levels, and the NLRP3 inflammasome were assessed. Molecular docking analysis and cellular thermal shift assay were conducted to evaluate the binding affinity of loganin to Sigma-1R. Additionally, the impact of a Sigma-1R inhibitor (BD1047) on loganin's effects was investigated. Loganin improved social isolation- and LPS-induced depressive-like behaviors. It also reduced astrocyte and microglia reactivity and decreased oxidative stress levels. Furthermore, loganin downregulated the expression of IRE1α, TXNIP, and the NLRP3 cascade. Molecular docking and cellular thermal shift assays confirmed strong binding of loganin to Sigma-1R. Loganin increased Sigma-1R expression in the hippocampus in response to LPS or social isolation. The antidepressant-like effects of loganin, as well as its inhibition of the NLRP3 inflammasome and oxidative stress, were reversed by BD1047. These findings suggest that loganin alleviates inflammation-associated depressive-like behaviors by inhibiting the NLRP3 inflammasome and oxidative stress via the Sigma-1R/IRE1α/TXNIP pathway, highlighting its potential as a therapeutic agent for inflammation-related depression.