Norisoboldine inhibits endoplasmic reticulum stress and alleviates depressive behaviors in CUMS mice by activating growth hormone secretagogue receptor type 1a in the hippocampus.

Depression is a common mental and mood disorder. Norisoboldine (NIB) has been shown to provide neuroprotective benefits. However, its potential antidepressant effects and underlying mechanisms remain to be elucidated. Our findings indicated that NIB ameliorates depressive behaviors and mitigates hippocampal neuronal damage induced by chronic unpredictable mild stress (CUMS). Numerous studies have corroborated the neuroprotective effects of gastrointestinal hormones such as ghrelin and its endogenous receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a). Notably, NIB demonstrated minimal impact on the expression levels of ghrelin and GHSR-1a. We furtherly investigated whether NIB could directly activate GHSR-1a in vitro. Treatment with NIB increased cell viability and inhibited CORT-induced apoptosis in HT-22 cells in a dose-dependent manner. The use of a GHSR-1a antagonist and GHSR-1a knockdown weakened the inhibitory effect of NIB on cell apoptosis. NIB attenuated endoplasmic reticulum (ER) stress via GHSR-1a in HT-22 cells, thereby protecting against cell apoptosis and loss. Molecular docking results showed an interaction between NIB and GHSR-1a, and CESTA results showed that NIB increased the thermal stability of GHSR-1a. In conclusion, NIB can reduce ER stress-induced injury to hippocampal neurons through GHSR-1a and improve depressive behavior in mice induced by CUMS.