Polysaccharides in the treatment of brain injury-related diseases: blood–brain barrier limitations and peripheral action pathways

Natural polysaccharides possess outstanding advantages including low toxicity, favorable biocompatibility, and multi-target regulatory capabilities. They hold broad application prospects in neuroprotective research on Alzheimer’s disease (AD) and depression. Owing to their high molecular weight and strong hydrophilicity, intact polysaccharides cannot readily cross the blood–brain barrier (BBB). Only a minor proportion enters the systemic circulation after oral administration. However, even under conditions of extremely low intracerebral exposure, polysaccharides still exhibit significant central neuroprotective effects. The underlying mechanism is that intact polysaccharides primarily act as fermentation substrates for gut microbiota, which then promote the production of short-chain fatty acids (SCFAs) and modulate tryptophan and bile acid metabolism. These peripheral metabolites, upon entering the circulation, further regulate peripheral immune responses and the activity of the hypothalamic–pituitary–adrenal (HPA) axis, improve neurotrophic signaling and redox homeostasis, and transmit signals to resident immune cells within the central nervous system via central boundary structures. Therefore, natural polysaccharides do not directly enter the brain. Instead, they exert neuroprotective effects via a cascade pathway involving the gut microbiota-peripheral metabolites-immune and humoral network. This article systematically elaborates on its multi-pathway mechanisms of action and summarizes adjunctive brain-targeted delivery approaches, including pathology-dependent modulation of BBB permeability and brain-targeted delivery. Future research should further elucidate the causal relationships among various signaling pathways, strengthen quality control and clinical trials, and facilitate their translational application.