Abstract: BACKGROUND: Dodder, as a traditional tonic herb in Chinese medicine, has anti-inflammatory and antidepressant properties, which may be involved in inhibiting neuroinflammatory cascades. However, whether this effect interferes with the neuroimmune imbalance mechanism of depression by specifically regulating pyroptosis and neuroinflammatory cascades mediated by the NLRP3/ASC/Caspase-1 signaling axis has not yet been systematically elucidated.
OBJECTIVE: To explore the therapeutic effect and mechanism of dodder in chronic stress depression mice based on NLRP3 inflammasome.  
METHODS: ICR mice were randomly divided into blank group, model group, paroxetine group (2.6 mg/kg) and dodder group (10.2 g/kg). The depression model was induced in the latter three groups by chronic unpredictable mild stress for 4 weeks. Sugar-water preference, forced swimming and tail hanging tests were used to detect depression-like behaviors. The levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and the contents of 5-hydroxytryptamine, dopamine and brain-derived neurotrophic factor in hippocampus were detected by ELISA. Western blot assay was used to analyze NLRP3/ASC/Caspase-1 protein expression. qRT-PCR was used to quantify the mRNA expression of interleukin-1β, NLRP3, ASC, and inducible nitric oxide synthase. The morphological changes of hippocampal neurons were observed by hematoxylin-eosin staining.  
RESULTS AND CONCLUSION: (1) Compared with the blank group, the model group showed significant depression-like behavior phenotype: the sugar-water preference rate was decreased to 46.4%, the immobility time of forced swimming was increased by 2.0-fold, and the rest time of tail suspension was increased by 2.9-fold (all P < 0.01). The density of neurons in the hippocampal CA3 region was decreased, and the pathological features included nuclear shrinkage, reduced dendritic branches and enlarged neuronal spaces. The levels of hippocampal inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, were significantly increased (P < 0.05), while the levels of neurotransmitters, 5-hydroxytryptamine, dopamine and brain-derived neurotrophic factor, were significantly decreased (P < 0.05). The relative expressions of NLRP3, ASC and Caspase-1 proteins related to inflammasome in the hippocampus of mice were significantly increased (P < 0.05). (2) Treatments with paroxetine and dodder significantly reversed the depression-like phenotype of mice: the sugar-water preference rate increased to 89.2%-95.1% in the blank group, the immobility time of forced swimming decreased to 65.27%, and the rest time of tail suspension decreased to 61.2% (all P < 0.05 vs. the model group). Hippocampal neurons were significantly recovered, and the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly decreased (P < 0.05), while the levels of 5-hydroxytryptamine, dopamine and brain-derived neurotrophic factor were significantly increased (P < 0.05). The relative expressions of NLRP3, ASC and Caspase-1 related to inflammasome in the hippocampus of mice were significantly decreased (P < 0.05). There was no significant difference between paroxetine group and dodder group (P > 0.05). In conclusion, dodder can improve depression-like behaviors in mice subjected to chronic unpredictable mild stress by inhibiting the activation of NLRP3 inflammasome, inhibiting hippocampal neuroinflammation, and increasing hippocampal neurotransmitter levels.

Key words: dodder, depression, hippocampus, NLRP3, chronic unpredictable mild stress, mouse