Monotropein alleviates sepsis-associated encephalopathy by targeting matrix metalloproteinase-9

Sepsis is a severe systemic infection that leads to multiple organ dysfunction and high mortality, making it one of the primary causes of death in ICU patients. Sepsis also induces septic encephalopathy (SAE), resulting in acute and long-term cognitive impairments. Research indicates that inhibiting BBB damage, anti-inflammatory, and antioxidant responses are critical therapeutic directions for SAE. Monotropein (Mon), the main active component of the traditional Chinese medicine Epimedium, possesses various pharmacological effects, including antioxidant properties. This study aims to explore the protective effects and potential targets of Mon in SAE. Firstly, the GEO database was utilized to screen for highly expressed genes, identifying matrix metalloproteinase-9 (MMP9) as a target. Drug target reverse screening using Schrodinger software confirmed MMP9 as a potential therapeutic target for Mon. Subsequently, in vitro experiments using an LPS-stimulated BV-2 and HUVECs co-culture model examined the interaction between Mon and MMP9. A CLP-induced mouse model was employed to investigate Mon's role in SAE. Results indicate that MMP9 is highly expressed in SAE and promotes its progression. Mon targets MMP9, enhancing its protein stability and exerting anti-inflammatory, improved vascular permeability, and barrier protective effects. Mon alleviates brain tissue damage, BBB disruption, and synaptic loss induced by CLP, increases antioxidant enzyme activity to eliminate ROS, and suppresses sepsis-induced oxidative stress, thereby mitigating CLP-induced cognitive impairment in mice. In conclusion, Mon targets MMP9, exerting anti-inflammatory, antioxidant, and barrier protective effects, alleviating SAE. Mon may serve as a potential natural therapeutic agent for treating sepsis-induced brain dysfunction.