Escitalopram attenuates spinal cord injury by suppressing NLRP3 inflammasome-mediated pyroptosis via PI3K/AKT pathway activation

Spinal cord injury (SCI), most often caused by trauma, is a debilitating disorder of the central nervous system, and it is characterized by motor, sensory, and autonomic impairments accompanied by extensive secondary damage. Although escitalopram (ESC) has demonstrated the ability to suppress lipopolysaccharide (LPS)-induced neuroinflammation in murine models, its role in SCI repair remains unclear. This study investigated the pharmacological effects of ESC in a traumatic SCI mouse model, integrating network pharmacology analysis and LPS-stimulated BV2 microglia to evaluate motor recovery and the expression of inflammation- and pyroptosis-related proteins. ESC treatment enhanced functional recovery, reduced the expression of pyroptosis-associated proteins, and attenuated post-injury inflammation. Network pharmacology identified core targets including MAPK3, AKT1, and Hsp90aa1, indicating that ESC exerts therapeutic effects mainly through the PI3K/AKT signaling pathway and other inflammation-related cascades. ESC reactivated PI3K/AKT signaling both in vivo and in vitro . Furthermore, the PI3K inhibitor LY294002 reversed the ESC-mediated suppression of pyroptosis in BV2 cells, indicating that ESC likely alleviated neuroinflammation by activating the PI3K/AKT signaling pathway following SCI. These findings position ESC as a promising therapeutic candidate for SCI management.