Progesterone attenuates depression-like behaviors in chronic unpredictable stress via suppression of...

Psychological stress has been implicated in triggering systemic inflammatory responses through dysregulation of cytokine networks, which represents a key mechanism involved in depression pathogenesis. Progesterone, a neuroactive steroid, exhibits neuroprotective properties and modulates central inflammatory processes; however, its therapeutic potential in stress-induced depression remains underexplored.

We established a depression model using Sprague-Dawley rats (n = 6) subjected to a 6-week chronic unpredictable mild stress (CUMS) paradigm. Following stress induction, animals received progesterone treatment for 2 weeks. Depression-like behaviors were assessed using the sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST). Systemic inflammation was evaluated by measuring serum levels of IL-1β and TNF-α using ELISA. NLRP3 inflammasome activation was analyzed via Western blot in prefrontal cortical and hippocampal tissues to quantify the protein expression of NLRP3, pro-caspase-1, and cleaved caspase-1.

CUMS-exposed rats demonstrated robust depressive phenotypes, with significant reductions in sucrose preference (22.65 %, p < 0.01), locomotor activity in the OFT (56.22 %%, p < 0.01), and immobility time in the FST (1057.57 %, p < 0.01) compared with controls. Progesterone administration reversed these behavioral deficits (all p < 0.05). Molecular analyses revealed that progesterone:Attenuated serum levels of pro-inflammatory cytokines (IL-1β: p < 0.01; TNF-α: p < 0.05). Suppressed CUMS-induced upregulation of NLRP3 in prefrontal cortex (p < 0.05) and hippocampus (p < 0.05). Inhibited caspase-1 activation by reducing pro-caspase-1 cleavage (prefrontal cortex: p < 0.01; hippocampus: p < 0.05).

Our findings demonstrate that progesterone ameliorates chronic stress-induced depression via multimodal mechanisms involving NLRP3 inflammasome inhibition, neuroinflammatory resolution, and neuronal protection. These results support progesterone as a promising therapeutic candidate for inflammation-associated depressive disorders.