Evaluation of modafinil's neuroprotective effects in lipopolysaccharide-induced sepsis-associated encephalopathy: associations with GSK3β, inflammatory, oxidative stress, and apoptotic signaling.

Sepsis is frequently accompanied by central nervous system involvement, leading to sepsis-associated encephalopathy characterized by neuroinflammation, microvascular dysfunction, and neuronal injury. Despite increasing recognition of its clinical impact, effective neuroprotective strategies remain limited. Modafinil (MOD), a wakefulness-promoting agent, has recently attracted attention for its anti-inflammatory, antioxidant, and neuroprotective properties in experimental models. Experimental sepsis was induced by intraperitoneal administration of lipopolysaccharide (LPS) in adult female Wistar rats. Animals were randomly assigned to four groups: control, LPS, LPS plus MOD, and MOD alone. Cerebral tissue was harvested six hours after LPS administration. Caspase-3 and tumor necrosis factor-alpha (TNF-α) expressions were assessed by immunohistochemistry. Oxidative stress was evaluated by measuring total oxidant status (TOS), total antioxidant status (TAS), and the oxidative stress index (OSI) in cerebral tissue homogenates. Gene expression levels of AKT1, glycogen synthase kinase 3 beta (GSK3B), sirtuin 1 (SIRT1), and heme oxygenase-1 (HO-1) were analyzed by quantitative PCR. LPS administration produced significant increases in Caspase-3 and TNF-α immunoreactivity in both cerebral cortex and cerebellum. At the oxidative stress level, LPS significantly elevated TOS and OSI while reducing TAS, indicating a pronounced shift toward pro-oxidant conditions. At the molecular level, LPS significantly increased GSK3B expression while reducing HO-1 expression. MOD treatment significantly reduced Caspase-3 and TNF-α immunoreactivity in both regions, restored the oxidative balance as evidenced by significantly attenuated TOS and OSI levels, and significantly suppressed GSK3B upregulation, whereas its effect on HO-1, AKT1, and SIRT1 expression did not reach statistical significance. MOD mitigates sepsis-induced cerebral and cerebellar injury by attenuating neuroinflammation, oxidative stress, and apoptosis. The accompanying decrease in GSK3B expression suggests that GSK3β-related signaling may contribute to these effects, although this relationship is associative rather than causal. MOD may therefore warrant further evaluation as a neuroprotective agent in sepsis-related CNS injury.