The ameliorative effects of gastrodin on cognitive impairment in STZ-treated mice are associated with the modulation of hippocampal neurogenesis-related proteins and inhibition of the AGEs–RAGE axis

Hippocampal neurogenesis has been implicated in diabetic cognitive impairment (DCI). Gastrodin (Gas), the major bioactive ingredient of Gastrodia elata, has anti-inflammatory, antioxidant, and neuroprotective activities. This study investigated whether Gas protects against DCI and whether this is associated with the AGEs–RAGE axis and hippocampal neurogenesis-related proteins. DCI was induced in mice by a high-fat diet plus streptozotocin. Mice received 25, 50, or 100 mg/kg Gas daily for four weeks, with metformin as positive control. Fasting blood glucose was monitored weekly. Gas attenuated hyperglycemia and cognitive deficits in DCI mice. Gas treatment was accompanied by upregulation of neurogenesis- and synaptic-related proteins (C-Myc, Cyclin D1, NGN2, NeuroD1, PSD95, MAP2) and downregulation of AGEs, RAGE, GFAP, and pro-inflammatory factors. These findings suggest that Gas may alleviate HFD/STZ-induced cognitive impairment, possibly via AGEs–RAGE axis suppression and enhanced hippocampal neurogenesis-related protein expression. However, this study was limited to a single animal model, relied mainly on correlative molecular data, and did not include pathway-blocking experiments. Further studies are needed to confirm causality and clinical relevance.