Icariside II, a Phosphodiesterase-5 Inhibitor, Attenuates Beta-Amyloid-Induced Cognitive Deficits via BDNF/TrkB/CREB Signaling.

Icariside II (ICS II) is an active component from Epimedium brevicornum, a Chinese medicine extensively used in China. Our previous study has proved that ICS II protects against learning and memory impairments and neuronal apoptosis in the hippocampus induced by beta-amyloid25-35 (Aβ25-35) in rats. However, its in-depth underlying mechanisms remain still unclear. Hence this study was designed to explore the potential underlying mechanisms of ICS II by experiments with an in vivo model of Aβ25-35-induced cognitive deficits in rats combined with a neuronal-like PC12 cells injury in vitro model. The cognitive deficits was measured using Morris water maze test, and apoptosis, intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected by TUNEL, DCFH-DA and Mito-SOX staining, respectively. Expression of Bcl-2, Bax, brain derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and cAMP response element binding (p-CREB) and active-Caspase 3 levels were evaluated by Western blot. It was found that ICS II, a phosphodiesterase-5 inhibitor, significantly attenuated cognitive deficits caused by Aβ25-35 injection in rats, and ICS II not only significantly enhanced the expression of BDNF and TrkB, but also activated CREB. Furthermore, ICS II also significantly abrogated Aβ25-35-induced PC12 cell injury, and inhibited Aβ25-35-induced intracellular reactive oxygen species (ROS) overproduction, as well as mitochondrial ROS levels. In addition, ICS II up-regulated the expressions of BDNF and TrkB consistent with the findings in vivo. ANA-12, a TrkB inhibitor, blocked the neuroprotective effect of ICS II on Aβ25-35-induced neuronal injury. ICS II mitigates Aβ25-35-induced cognitive deficits and neuronal cell injury by upregulating the BDNF/TrkB/CREB signaling, suggesting that ICS II can be used as a potential therapeutic agent for dementia, such as Alzheimer's disease.