Mechanistic insights into the effects of Norisoboldine on intestinal immunity and neuroinflammation in a mouse model of slow transit constipation with depression.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Norisoboldine (NOR), an isoquinoline alkaloid extracted from the traditional Chinese medicinal herb Lindera aggregata (Sims) Kosterm., has been historically used for the treatment of rheumatism, abdominal pain, and gastrointestinal disorders. Its potential for modulating gut-brain axis function in the context of coexisting constipation and depression remains largely unexplored. AIM OF THE STUDY: To investigate the therapeutic efficacy and underlying mechanisms of Norisoboldine in a mouse model of slow transit constipation (STC) with comorbid depression, with emphasis on intestinal immune regulation and neuroinflammation. MATERIALS AND METHODS: A mouse model of STC with depression was established using loperamide in combination with chronic unpredictable mild stress (CUMS). Mice were orally administered NOR for 14 days. Behavioral tests, stool parameters, and histological analysis were conducted. Flow cytometry was used to quantify intestinal immune cell subsets (ILC3s, Th1, Tregs). The expression of inflammatory cytokines in the colon and hippocampus was assessed via qRT-PCR, Western blotting, and immunofluorescence. The involvement of NF-κB signaling pathways was also examined. RESULTS: NOR significantly improved stool frequency, intestinal transit, and depressive-like behaviors in STC-depressed mice. It restored intestinal immune homeostasis by increasing ILC3s and Tregs and decreasing Th1 cells. NOR reduced inflammatory cytokine expression in both the colon and hippocampus, and inhibited NF-κB signaling pathway. CONCLUSIONS: Norisoboldine ameliorates gastrointestinal and neuropsychiatric symptoms in STC with depression by regulating intestinal immune balance and suppressing neuroinflammation. These findings support the potential of NOR as a candidate therapeutic agent for gut-brain axis-related disorders, aligning with its traditional ethnomedicinal applications.