Icariside II, a PDE5 inhibitor from Epimedium brevicornum , promotes neuron-like pheochromocytoma PC12 cell proliferation via activating NO/cGMP/PKG pathway

Abstract

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.

Icariside II, a PDE5 Inhibitor, Suppresses Oxygen-Glucose Deprivation/Reperfusion-Induced Primary Hippocampal Neuronal Death Through Activating the PKG/CREB/BDNF/TrkB Signaling Pathway

“…Thus, targeting PDE5 is a promising strategy for treating neurological diseases, such as stroke and AD. Intriguingly, this study showed that ICS II significantly attenuated the expression and activity of PDE, while it increased cGMP level and PKG activity, consisting with our previous study (Gao et al, 2017;Gao et al, 2018). Furthermore, the favorable effects of ICS II were almost abolished by Rp-8-Br-cGMP, a PKG inhibitor, which further confirmed that ICS II protected against OGD/R-induced neuronal injury through regulating cGMP-dependent pathway.…”

Icarisid II promotes proliferation and neuronal differentiation of neural stem cells via activating Wnt/β‐catenin signaling pathway

“…## p < .01 versus NSCs; *p < .05, **p < .01 versus APP-NSCs; & p < .05, && p < .01 versus APP-NSCs+ICS II [Colour figure can be viewed at wileyonlinelibrary.com] Wnt/β-catenin signaling pathway. In addition to our findings, ICS II has been reported to promote hippocampal neuron axon regeneration in rat suffering from chronic cerebral hypoperfusion (Liu et al, 2019), enhance the proliferation of neuron-like pheochromocytoma PC12 cell (Gao et al, 2018), as well as ameliorate memory impairments by reducing beta-amyloid (Aβ) production in APP/PS1 mice (L. Yan et al, 2017). An interesting study showed that ICS II treatment for 4 weeks enhanced endogenous stem cells differentiation to alleviate the erectile dysfunction in rat model of postprostatectomy (Xu et al, 2015).…”

“…Yan et al, 2017). It was also reported that ICS II can stimulate the proliferation of PC12 cells, and strengthen the axon regeneration of hippocampal neurons in rats suffering from chronic cerebral hypoperfusion (Gao, Xu, Lei, Shi, & Gong, 2018;Liu, He, Yan, Kuang, & Yu, 2019). In our previous study, we found that Shenzaojiannao oral liquid (SZJN), an herbal formula consists of Epimedii Folium and other herbal medicines, remarkably promoted NSCs proliferation and neuronal differentiation in vitro and in AD model mice (Xiao et al, 2020).…”

Sildenafil Recovers Burn-Induced Cardiomyopathy

“…This adjusts Rho kinase (ROCK), RGS2 and myosin phosphatase targeting subunit (MYPT) [30]. PDE5A inhibition raises cGMP levels, leading to downstream effects on the heart and vasculature [31]. PDE5A inhibitors may also inhibit RhoA-Rho kinase [14].…”