Effects and mechanism of berberine in ameliorating microglia-mediated hypothalamic inflammation by downregulating the MAPK and NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine (BBR), an isoquinoline alkaloid found in several plants, including Coptis chinensis, Phellodendron amurense, and various Berberis species, has been traditionally used to treat excessive thirst, abdominal distension, diarrhea, and jaundice. Recent studies have highlighted its anti-inflammatory and neuroprotective activities. However, its role in regulating hypothalamic inflammation via microglial polarization remains inadequately defined.

AIM OF THE STUDY: To elucidate the mechanisms by which BBR modulates hypothalamic inflammation in metabolic disorders.

MATERIALS AND

METHODS

Mice fed an obesogenic high-fructose high-fat diet (HFHFD) received oral BBR treatment for 4 weeks. Biochemical and histopathological analyses were performed to assess treatment effects. Inflammatory and signaling proteins were quantified by Western blotting, RT-PCR, and immunofluorescence. In vitro, BV2 microglia were stimulated with lipopolysaccharide (LPS) to model neuroinflammation. The p38 MAPK inhibitor SB203580 was used, and soluble mediators and protein markers were measured by the Griess assay, Western blotting, and immunofluorescence. Neuroprotective effects were further assessed in co-culture with GT1-7 neuronal cells.

RESULTS

BBR improved glucose and lipid metabolism in HFHFD mice. It suppressed phosphorylation of IKKβ, NF-κB, p38 MAPK, and ERK1/2 within the MAPK/NF-κB pathway in the hypothalamus, thereby promoting microglial polarization from the M1 to the M2 phenotype. In vitro, BBR attenuated LPS-induced microglial inflammation. Use of the p38 MAPK inhibitor confirmed that BBR alleviates hypothalamic inflammation by increasing the M2/M1 ratio via the MAPK pathway. Moreover, BBR enhanced GT1-7 cell survival, indicating neuroprotective activity.

CONCLUSION

BBR may mitigate hypothalamic inflammation and metabolic dysfunction in HFHFD mice by promoting a shift from M1 to M2 microglial phenotypes via MAPK/NF-κB signaling.