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Post-stroke chronic stress (PSCS) is generally associated with the poorer recovery and more pronounced cognitive dysfunction. Recent evidence has implied that S-ketamine can reduce suicidal ideation in treatment-resistant depression. In this current study, we aimed to investigate whether the administration of S-ketamine ameliorated cognitive deficits under PSCS conditions, which was established by a model combining middle cerebral artery occlusion (MCAO) and chronic restraint stress. Our data suggested that mice exposed to PSCS exhibited depression-like behavior and cognitive impairment, which coincided with astrocytosis as indicated by increased GFAP-positive cells and impairment of long-time potentiation (LTP) in the hippocampal CA1. Subanesthetic doses (10 mg/kg) of S-ketamine have significantly mitigated depression-like behaviors, cognitive deficits and LTP impairment, reduced astrocytosis, excessive GABA, and inflammatory factors, including NLRP3 and IL-18 in astrocytes in the CA1. Besides, neuroprotective effects induced by S-ketamine administration were found in vitro but could be partially reversed by an agonist of the NLRP3 nigericin. Our current data also suggests that the subanesthetic doses of S-ketamine improved cognitive dysfunction via the inhibition of hippocampal astrocytosis in a mouse model of PSCS. [ABSTRACT FROM AUTHOR]

• Sulfuretin dose-dependently decreased immobility times. • Sulfuretin restored BDNF levels and ERK signaling. • Sulfuretin improved brain function. : Herb-derived therapeutics is an attractive strategy to treat depression. Here we report the ameliorating effects of Sulfuretin, an anti-inflammatory compound in a depressive mouse model. : Immobility times were obtained in the tail suspension test and forced swim test performed from day 14 to day 16. Quantitative real-time PCR (qRT-PCR) and Western blot were used to measure brain-derived neurotrophic factor (BDNF) and the extracellular signal-regulated kinase (ERK) pathway of the hippocampus tissue on day 17. SL327 was used to block the ERK pathway in mice to evaluate the interaction between Sulfuretin and the ERK pathway. Mice were treated with Sulfuretin for 14 days before lipopolysaccharide (LPS) injection (0.83 mg/kg/day, i.p.) for two days. : Behavior tests showed that Sulfuretin dose-dependently decreased immobility times correlated with depression symptoms. BDNF levels and ERK signaling were significantly restored in the Sulfuretin-treated mice, showing the improvement of brain function. Blocking the p-ERK signaling abrogated the effects of Sulfuretin in improving behaviors and levels of BDNF. : Our study suggests that Sulfuretin exhibits anti-depressive function in LPS-induced depressive mice, in which the ERK signaling plays an essential role. [ABSTRACT FROM AUTHOR]