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Icariside II (ICS II), a phosphodiesterase 5 inhibitor (PDE 5-I), is a major ingredient of Epimedium brevicornum, with wide spectrum of neuroprotective properties. However, little is known about the potential beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanism remains still unclear. We hypothesized that the beneficial effect of ICS II on neuron-like highly differentiated rat pheochromocytoma (PC12) cell proliferation is correlated with the nitric oxide (NO) signaling pathway and its upstream of PI3K/AKT pathway. PC12 cells were treated with ICS II alone or together with L-NMMA, H89, KT-5823, and/or LY294002 (the inhibitor of NOS, PKA, PKG, PI3K, respectively). It was found that ICS II concentration-dependently promoted PC12 cells proliferation, and cell cycle analysis showed that the proportion of ICS II-treated PC12 cells in S phase was higher than that of control. Moreover, ICS II at the appropriate concentration (100 μM) not only increased nNOS expression, NO production, but also enhanced cGMP content and PKG activity. The addition of L-NMMA and KT-5 823 significantly inhibited the effects of ICS II on nNOS expression, NO production and PKG activity. Furthermore, LY294002 significantly decreased p-AKT level, NOS activity, NO production and nNOS expression, but it did not affect iNOS expression. These findings demonstrate that the beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanisms are, at least partly, through activating AKT/nNOS/NO/cGMP/PKG signaling pathway.ICS II promotes PC12 cell proliferation.The beneficial effect of ICS II on neuronal cell proliferation is due to increasing NO level.ICS II not only activates AKT to increase NO level, but also inhibits PDE5 activity to suppress the degradation of NO.ICS II will be a promising candidate for treating neurodegenerative diseases.