Huperzine A (Hup A) is a lycopodium alkaloid from Huperzia serrata, which has been used as a therapeutic agent in several neurological disorders. Despite the diverse pharmacological activities Hup A has, its role in hippocampal neurogenesis remains to be established. This study showed that Hup A not only promoted the proliferation of cultured mouse embryonic hippocampal neural stem cells (NSCs), but also increased the newly generated cells in the subgranular zone (SGZ) of the hippocampus in adult mice. Furthermore, the in vitro findings indicated that low concentrations of Hup A stimulated the proliferation of cultured NSCs, whereas extremely high concentration of it decreased the cell proliferation. Hup A activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which was a well-known regulator of biological processes including cell proliferation and differentiation. ERK inhibitor dramatically inhibited the proliferative effect of Hup A on NSCs. Administration of Hup A to adult mice significantly enhanced the cell proliferation in dentate gyrus of hippocampus, and increased the remaining newborn cells 4 weeks after the drug administration. Moreover, the newly generated BrdU(+)/NeuN(+) neurons were also increased by Hup A treatment. These findings suggest a novel role of Hup A in neurogenesis and provide a new insight into its therapeutic effects in neurological disorders via a neurogenesis-related mechanism.
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