Neuroinflammation and fever are the main triggers in febrile seizures (FS). Focusing on inflammatory pathways and anti-inflammatory drugs could compensate for the limitations of existing medications. The aim of this study is to evaluate the neuroprotective effect of specific antagonizing Toll-like receptor 4 (TLR4), as a prominent inflammatory axis, on the consequences of FS and adulthood using animal models. Complex FS was induced on 9 to 11 day old male rat pups using a heated chamber. TAK-242, as a specific TLR4 inhibitor, was injected intraperitoneally before seizure induction. Seizure threshold, duration, and spike number were measured by electrocorticography. The levels of inflammatory cytokines, TLR4 protein expression, and oxidative stress markers were detected by enzyme-linked immunosorbent assay, western blotting, malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) assessments in the cortex and hippocampus. Also, spatial and non-spatial memory were evaluated using the novel object recognition test (NORT) and double Y-maze test during adulthood. The results revealed that provoked inflammatory responses in neonate rats, after FS, were associated with the increase of the tumor necrosis factor alpha, interleukin-1β, and enhanced TLR4 protein expression. Meanwhile, based on performed behavioral tests, the inflammatory process was also involved in adulthood memory deficit. Pretreatment with TAK-242 reduced the inflammatory cytokines and TLR4 protein expression in the cortex and hippocampus of neonate rats and improvement in memory deficit in NORT and double Y-maze tasks. Also, pretreatment with TAK-242 elevated seizure threshold, SOD, and CAT activities, and decreased seizure duration and MDA level with no significant change in spike number. TAK-242 possibly controlled FS via inhibiting inflammation.

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