Icariin Alleviates Diabetes-Associated Cognitive Dysfunction Through Modulation of LCN2-MEK/ERK Signaling-Associated...

Diabetes-associated cognitive dysfunction (DACD) is a severe neurological complication of diabetes, yet effective preventive or therapeutic strategies remain limited. Icariin (ICA), a dietary-derived natural flavonoid, has suggested potential neuroprotective properties in other diseases. However, its specific effects and underlying mechanisms in DACD are not fully elucidated. This study aimed to investigate the protective effects of ICA in DACD and to clarify its multi-target mechanisms involving neuroinflammatory signaling.

We explored the differentially expressed proteins between DACD and diabetes mellitus without cognitive dysfunction (DM-noCD) patients through proteomics and validated them by ELISA. We adopted an integrated research strategy combining in vivo and in vitro experiments. In vivo, db/db diabetic mice were orally administered ICA for 4 weeks. Cognitive function was evaluated using behavioral tests, hippocampal neuroinflammation was assessed by immunofluorescence and measurement of inflammatory cytokine levels, and the regulatory effect of ICA on the LCN2-MEK/ERK signaling pathway was evaluated through molecular biological methods. In vitro, high glucose-stimulated HT22 hippocampal neuronal cells were utilized to validate the role of the key LCN2-MEK/ERK pathway via LCN2 knockdown experiments.

ICA treatment significantly improved spatial learning and memory deficits in db/db mice. It alleviated hippocampal neuroinflammation, significantly downregulated hippocampal LCN2 expression, and inhibited phosphorylation of the MEK/ERK pathway. In HT22 cells, high glucose stimulation increased LCN2 expression and activated the MEK/ERK pathway, exacerbating inflammatory responses; ICA treatment counteracted these effects. Moreover, LCN2 knockdown suppressed MEK/ERK pathway activation, and ICA treatment induced no further changes under these conditions, suggesting that the inhibitory effect of ICA on this pathway is dependent on the presence of LCN2.

This study suggests that ICA ameliorates DACD by targeting the LCN2-MEK/ERK signaling pathway while alleviating neuroinflammation. These findings highlight the protective effects of ICA on DACD and its potential in other neurodegenerative disorders that may be associated with metabolic dysregulation.