Abstract
BACKGROUND: Temporal lobe epilepsy (TLE) is frequently associated with cognitive impairments, such as memory deficits, attention disorders, and executive dysfunction. Given that these cognitive deficits are closely linked to neuronal loss in TLE, fibroblast growth factor 10 (FGF10), a molecule recognized for its neuroprotective properties, has emerged as a promising therapeutic candidate. The kainic acid (KA)-induced epilepsy model can replicate key pathological features of TLE. The study aims to investigate the potential role of FGF10 in TLE, using the KA-induced model as an experimental framework. METHODS: We induced epilepsy in mice using KA and administered intranasal FGF10 over 14 days or delivered an AAV virus to overexpress FGF10. Seizure activity was monitored via video-electroencephalography (EEG), and behavioral tests were conducted to assess spatial cognition, anxiety-related behaviors, and depressive-like behaviors. Neuronal damage was evaluated using Nissl staining and TUNEL staining. To explore the molecular mechanisms underlying FGF10's effects, we performed RNA sequencing, followed by validation with Western blotting and qRT-PCR. Additionally, we generated FGFR2 conditional knockout (cKO) mice to investigate the role of FGF10-FGFR2 signaling. RESULTS: FGF10 treatment significantly reduced seizure frequency and improved epilepsy-related cognitive deficits. It also exerted neuroprotective effects, as evidenced by reduced neuronal death in KA-induced epileptic mice. RNA sequencing revealed decreased CALB1 levels in the hippocampal dentate gyrus of epileptic mice, which were restored following FGF10 administration. Crucially, the therapeutic benefits of FGF10 were abolished in FGFR2-cKO mice, indicating that FGFR2 is essential for FGF10's effects. CONCLUSIONS: Our findings demonstrate that FGF10 alleviates seizures and cognitive dysfunction in epilepsy, likely through FGFR2-dependent mechanisms involving CALB1 modulation. These results highlight FGF10 as a potential therapeutic target for epilepsy, offering a novel strategy for improving treatment outcomes in patients with TLE.