Behav Brain Res. 2025 Oct 16:115879. doi: 10.1016/j.bbr.2025.115879. Online ahead of print.
ABSTRACT
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.
PMID:41109630 | DOI:10.1016/j.bbr.2025.115879
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