Remimazolam alleviates blood-brain barrier damage by regulating the PI3K/AKT signaling pathway in sepsis-associated encephalopathy mice

Sepsis-associated encephalopathy (SAE) is a common neurological complication in critically ill patients. However, therapeutic strategies for SAE remain limited. Increasing evidence suggests that impairment of the blood-brain barrier (BBB) plays a crucial role in the progression of SAE. Remimazolam has been demonstrated in previous studies to exert neuroprotective effects through the modulation of neuroinflammatory responses. This study aimed to determine whether remimazolam alleviates BBB disruption in a murine model of SAE and to elucidate the underlying signaling mechanisms. A murine model of SAE was established by intraperitoneal administration of lipopolysaccharide (LPS), followed by treatment with remimazolam. To investigate the involvement of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, the specific PI3K inhibitor LY294002 was co-administered. BBB integrity, expression of ZO-1 and Occludin, levels of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6), and microglial activation were systematically evaluated. Our results indicate that LPS increases blood-brain barrier permeability, downregulates the expression of ZO-1 and Occludin, elevates brain levels of pro-inflammatory cytokines IL-1β and IL-6, and induces microglial activation. In contrast, remimazolam treatment significantly attenuated LPS-induced BBB dysfunction, as evidenced by reduced Evans blue extravasation, restoration of ZO-1 and Occludin expression, decreased production of IL-1β and IL-6, and suppression of microglial overactivation. Moreover, remimazolam reversed LPS-induced inhibition of the PI3K/AKT signaling pathway. Notably, co-administration of LY294002 abolished the protective effects of remimazolam, indicating a critical role for PI3K/AKT signaling in mediating its neuroprotective actions. These findings suggest that remimazolam may represent a promising therapeutic candidate for targeting the pathogenesis of SAE.