Dihydromyricetin protects hippocampal neurons in sepsis-associated encephalopathy by reducing ER stress-mediated apoptosis and inflammation.

Sepsis-associated encephalopathy (SAE) involves hippocampal dysfunction and cognitive deficits, but its underlying mechanisms remain unclear, and effective treatments are lacking. Dihydromyricetin (DHM), a key flavonoid in Japanese raisin trees and Chinese Rattan tea, exhibits broad therapeutic potential for neurological disorders. This study investigated whether DHM improves hippocampal dysfunction in SAE rats by targeting endoplasmic reticulum (ER) stress-mediated apoptosis and inflammation. The SAE model was established by cecal ligation perforation (CLP) surgery in rats. We evaluated survival rates, exploratory activity, cognitive behavior, hippocampal histopathology, neuronal apoptosis, pro-inflammatory cytokine levels, and ER stress pathway activation in CLP-induced SAE rats. SAE rats exhibited severe cognitive impairment, hippocampal damage, elevated inflammation, and reduced survival rates. CLP surgery also activated all three branches of the ER stress pathway and significantly increased hippocampal NF-κB and HMGB1 expression. In contrast, DHM treatment effectively suppressed ER stress activation and subsequent inflammatory responses, reduced neuronal apoptosis, preserved hippocampal structure, improved survival rates, and reversed cognitive deficits of SAE rats. Our findings demonstrate that DHM protects against SAE by inhibiting ER stress-induced neuronal apoptosis and inflammatory responses, thereby improving hippocampal cognitive function. These results highlight DHM as a promising therapeutic agent for SAE.