Depression frequently manifests as a secondary affective disorder in individuals who have experienced a stroke. In laboratory rats subjected to stroke, prolonged exposure to chronic stress effectively replicates the physiological impairment and adverse environmental challenges encountered by stroke patients. Nevertheless, the complex mechanisms underlying these phenomena remain unclear.

To elucidate the mechanisms underlying these impairments, we established a poststroke depression model by combining middle cerebral artery occlusion (MCAO) with 70 minutes of ischemia and chronic unpredictable mild stress (CUMS) exposure. Behavioral assessments, along with analyses of purinergic ligand-gated ion channel 7 receptor (P2X7R) and nucleotide-binding oligomerization domain, leucine-rich repeats, and pyrin domain-containing protein 3 (NLRP3)-associated inflammatory protein levels and peripheral blood inflammatory cytokine levels, were conducted at 1, 2 and 4 weeks post-MCAO, and the results were compared with those of rats subjected to stroke alone.

Depression-like behaviors were induced by CUMS exposure for three weeks. These changes were accompanied by significant increases in the protein levels of interleukin-1β (IL-1β), caspase-1, NLRP3 and Iba-1 in the hippocampus. Additionally, an increase in the fluorescence intensity of Iba-1, P2X7R, and NLRP3 in the Cornu Ammonis 1 (CA1) region was observed, along with dysregulation of plasma IL-6, IL-4, IL-10, and IL-1β levels. Importantly, the interaction of CUMS exposure and time affected behavioral scores and the levels of IL-1β. Notably, intraperitoneal administration of Brilliant blue G reversed depression-like behaviors and reduced the expression of NLRP3, caspase-1, IL-1β and IL-18 in the affected hippocampus.

These findings are consistent with the involvement of P2X7R/NLRP3 signaling in hippocampal impairment and inflammation/immune dysregulation in the context of depression-like behaviors induced by CUMS. In particular, behavioral scores may be affected by the interaction between CUMS exposure and time.