Antiseizure effects of Lilii Bulbus on pentylenetetrazol kindling-induced seizures in mice: Involvement of Reelin, Netrin-1, and semaphorin

Lilii Bulbus (Lilium lancifolium Thunberg) has a proneurogenic effect on the hippocampus. However, its effects on epilepsy and associated pathological features remain unknown. In this study, we investigated the antiseizure effects of a water extract of Lilii Bulbus (WELB) in mouse model of pentylenetetrazol (PTZ)-induced seizure. Mice were injected with PTZ once every 48 h until full kindling was achieved. WELB (100 and 500 mg/kg) was orally administered once daily before PTZ administration and during the kindling process. We found that WELB treatment protected against PTZ-induced low seizure thresholds and high seizure severity. Further, WELB-treated mice showed attenuated PTZ kindling-induced anxiety and memory impairment. Immunostaining and immunoblots showed that hyperactivation and ectopic migration of dentate granule cells (DGCs) were significantly reduced by WELB treatment in PTZ kindling-induced seizure mice. Staining for mossy fiber sprouting (MFS) using Timm staining and ZnT3 showed that WELB treatment significantly decreased PTZ kindling-induced MFS. Furthermore, the increased or decreased expression of proteins related to ectopic DGCs (Reelin and Dab-1), MFS (Netrin-1, Sema3A, and Sema3F), and their downstream effectors (ERK, AKT, and CREB) in the hippocampus of PTZ kindling mice was significantly restored by WELB treatment. Overall, our findings suggest that WELB is a potential antiseizure drug that acts by reducing ectopic DGCs and MFS and modulating epileptogenesis-related signaling in the hippocampus. [Display omitted] •WELB reduced PTZ kindling-induced seizure in mice.•WELB ameliorated PTZ kindling-induced anxiety and memory loss.•WELB inhibited ectopic DGCs and MFS in PTZ kindling-induced seizure mice.•Alterations of Reelin/Dab-1 and Netrin-1/Sema3A/Sema3F expression were restored by WELB treatment.•WELB has the anti-seizure effects on seizure severity and epileptogenesis-related factors.