A Drug Repurposing-Based Mechanistic study of ilepcimide against febrile seizures.

Febrile seizures are the most common childhood paroxysmal neurological disorder. Although ilepcimide is used for pediatric epilepsy, its efficacy in febrile seizures remains unknown. Here, we investigated the effects and mechanisms of ilepcimide in a juvenile mouse model of febrile seizures using network pharmacology, molecular docking, brain slice electrophysiology and patch-clamp recordings of transfected cells. Ilepcimide prolonged seizure latency and reduced EEG spike-wave frequency. Network pharmacology linked its targets to glutamatergic synaptic signaling. Molecular docking further predicted that ilepcimide could target two subunits of AMPA receptor. In acute hippocampal slices, ilepcimide suppressed CA1 pyramidal neuron firing, increased rheobase, and prolonged action potential half-width. In HEK293T cells expressing GluA1/GluA2, it prolonged AMPAR deactivation and desensitization time constants. These results suggest that ilepcimide protects against febrile seizures through a multi-faceted mechanism: modulation of glutamatergic transmission, reduction of hippocampal excitability, and altered AMPA receptor gating. This study offers new target predictions and experimental evidence supporting the extended use of ilepcimide in pediatric febrile seizures.