11,12-Diacetyl-Carnosol Ameliorates Depression-Like Behaviors and Memory Dysfunction in CUMS Mouse Model via Inhibiting HMGB1-Mediated Neuroinflammation

Backgrounds

11,12-Diacetyl-carnosol (DACA), a derivative of carnosol, exhibits significant anti-inflammatory and antioxidant properties. However, its antidepressant effects and underlying mechanisms remain unclear. High mobility group box 1 protein (HMGB1)-mediated inflammatory responses and associated neurofunctional impairments play a crucial role in the pathogenesis of depression. This study aimed to investigate whether DACA exerts anti-inflammatory and antidepressant effects and whether its mechanisms involve the HMGB1/NF-κB/NLRP3 signaling pathway.

Methods

(1) A depression model was established in mice through 6 weeks of chronic unpredictable mild stress (CUMS). From the 4th week of stimulation, the treatment group received DACA for 3 weeks. (2) BV2 cells were stimulated with LPS+ATP, and the treatment group was cultured in DACA medium for 24 h. (3) Supernatants from BV2 cells were used to culture primary neurons. To confirm the critical role of HMGB1 in DACA's antidepressant effects, CUMS-stressed mice were treated with glycyrrhizin (GZA) or the DACA+GZA combination. Depressive-like behaviors were evaluated using the sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), forced swim test (FST), and Morris water maze (MWM). Hippocampal microglial cell and primary neuron morphology were assessed by immunofluorescence, and dendritic spine density in hippocampal neurons was examined using Golgi staining. IL-6 and TNF-α concentrations in mouse serum and BV2 supernatant were measured by ELISA. Western blotting was used to detect protein expressions of HMGB1, NF-κB p65, p-NF-κB p65, NLRP3, and IL-1β in the hippocampus and BV2 cells.

Results

CUMS-exposed mice showed decreased sucrose preference, increased immobility in TST and FST, prolonged escape latency in MWM, and reduced crossings. Microglial activation and upregulation of HMGB1, NF-κB p65, p-NF-κB p65, NLRP3, and IL-1β were observed in both CUMS-stressed mice and LPS+ATP-induced BV2 cells, with reduced dendritic spine density in the hippocampus. DACA significantly reversed these phenomena. The effects of DACA were comparable to those of GZA treatment, and no changes were observed with the DACA+GZA combination.

Conclusion

The HMGB1/NF-κB/NLRP3 signaling pathway is involved in DACA's therapeutic effects on depression.