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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.

Lilii Bulbus, the bulb of tiger lily, has anti-oxidant and anti-tumorigenic properties. However, the effects of Lilii Bulbus on learning, memory, and hippocampal neurogenesis remain unknown. This study investigated whether water extract of Lilii Bulbus (WELB) affects memory ability and hippocampal neurogenesis. Behavioral analyses (Morris water maze and passive avoidance test), immunohistochemistry, cell proliferation assay, and immunoblot analysis were performed. WELB (50 and 100 mg/kg; for 14 days) enhanced memory retention and spatial memory in normal mice as well as in scopolamine-treated mice with memory deficits. Furthermore, the administration of WELB significantly increased the number of proliferating cells and surviving newborn cells in the dentate gyrus of the hippocampus in normal mice. We found that WELB has a pro-neurogenic effect by increasing the activation of brain-derived neurotrophic factor (BDNF)/cAMP response element-binding protein (CREB) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) in the hippocampus. Moreover, we confirmed that WELB (100 and 200 μg/ml) significantly increased NE-4 C and primary embryonic NSCs proliferation. Inhibition/knockdown of MEK/ERK blocked WELB-induced MEK/ERK phosphorylation and NSCs proliferation. Hence, MEK/ERK activation was required in WELB-induced NSCs proliferation. Our study demonstrates the first evidence for WELB promoting hippocampal neurogenesis and memory; pro-neurogenic activity may enhance brain plasticity, with implications for treating neurodegenerative diseases.