Inulin-Type Hexasaccharide Improves Vascular Dementia by Modulating Sphingomyelin Lipid Metabolism

Vascular dementia (VaD) is the second most common type of dementia lacking effective treatments. Inulin-type hexasaccharide (IHS) extracted from traditional Chinese herbal medicine BaJiTian (Morinda officinalis) has antidepressant effects in many animal models. In this study, we aimed to investigate the therapeutic effects and potential mechanisms of IHS in VaD. Our results showed that IHS could effectively improve cognitive impairment in VaD mice, alleviate histological changes, and promote cerebral blood flow recovery. In addition, we observed that IHS could reduce neuroinflammation and apoptosis in VaD mice. The comprehensive characterization analysis of the serum, fecal, and brain tissue metabolites revealed that IHS regulates multiple metabolic pathways including sphingolipid metabolism, glycerophospholipid metabolism, and pyruvate metabolism in VaD mice. Furthermore, integrative analysis of metabolomics and brain proteomics found that IHS modulates the sphingolipid metabolism pathway to decrease accumulation of ceramide in the brains of VaD mice. Based on the role of ceramide in VaD development and cognitive impairment, IHS improves the pathology of VaD mice at least partially through the sphingolipid metabolism pathway. These results provide a framework for better understanding the mechanisms of the therapeutic effects of IHS in VaD.

The online version contains supplementary material available at 10.1007/s43657-025-00262-5.