NGF-Hydrogel Ameliorates Aberrant Adult Hippocampal Neurogenesis and Improves Hippocampal Remodeling After Epilepsy

Temporal lobe epilepsy (TLE) is a common drug-resistant epilepsy characterized by recurrent seizures, cognitive impairment, aberrant adult hippocampal neurogenesis, inhibitory circuit disruption, and persistent inflammatory remodeling. Current anti-seizure medications primarily offer symptomatic control and do not target the progressive structural and functional deterioration of epileptic hippocampal networks. Here, we investigated whether local nerve growth factor (NGF)-hydrogel delivery during the latent phase after status epilepticus could mitigate hippocampal pathological remodeling and improve long-term outcomes in a kainic acid (KA)-induced mouse model (utilizing C57BL/6J and Nestin-CreERT2 mice). Animals were randomly assigned to three groups: the saline control group, the untreated KA epilepsy group, and the KA + NGF-hydrogel treatment group. NGF-hydrogel was administered into hippocampal Cornu Ammonis 1 (CA1) beginning 3 days post-kainic acid and repeated every 15 days. Histological, immunofluorescence, circuit-tracing, electrophysiology, electroencephalography (EEG), and behavioral assessments were used to evaluate neurogenesis, microenvironment, circuit readouts, seizure burden, and cognition. NGF-hydrogel treatment was associated with preserved dentate gyrus neural stem cell populations, improved newborn granule cell localization and maturation, attenuated neuroinflammation and gliosis, and partial recovery of inhibitory interneuron markers. These changes were accompanied by improved hippocampal circuit readouts, reduced chronic spontaneous seizure burden, and enhanced recognition and spatial memory. Our findings indicate that local NGF-hydrogel delivery following status epilepticus is associated with improved hippocampal remodeling and functional outcomes, and suggest that biomaterial-based neurotrophic support may be a promising strategy for providing targeted neuroprotection and facilitating excitatory/inhibitory (E/I) balance reconstruction in the epileptic hippocampus.