摘要:OBJECTIVE To explore the effects and mechanism of icariside Ⅱ(ICS Ⅱ),a pharmacologically active compound derived from herbal Epimedii with previous study-proved phosphodiesterase 5(PDE5) inhibitors,was investigated in vivo using a middle cerebral artery occlusion/reperfusion(MCAO/R) model in rats and in vitro using an oxygen-glucose deprivation/reperfusion(OGD/R) model in primary hippocampal neurons.METHODS Laser Doppler flowmeter was introduced to examine the cerebral blood flow of MCAO/R rats.The neurological deficits scores,brain water content and infarction volume were assessed after MCAO/R.OGD/R-induced primary hippocampal neuronal injury and apoptosis were examined by MTT,lactate dehydrogenase(LDH) release,TUNEL staining and flow cytometry,respectively.Expressions of PDE5 A and memory-related signaling pathways were measured using Western blotting analysis.The direct interaction between ICS Ⅱand PDE5 was further evaluated by molecular docking.RESULTS ICS Ⅱ significantly decreased the infraction volume in MCAO/R rats.Furthermore,ICS Ⅱ significantly abrogated OGD/R-induced hippocampal neuronal death.Moreover,ICSⅡ not only effectively restored the 3′ 5′-cyclic guanosine monophosphate(cGMP) level and protein kinase G(PKG) activity both in vivo and in vitro,but also increased brain-derived neurotrophic factor(BDNF),tyrosine protein kinase B(TrkB) and cAMP response element-binding protein(CREB) expressions,thereby inhibited hippocampal neuronal apoptosis.Mechanistically,the beneficial effects of ICS Ⅱ was attributed to its activation of the PKG/TrkB/BDNF via increasing BDNF expression,evidenced by that the inhibition effects of ICSⅡ was abrogated by Rp-8-BrcGMPS,a PKG inhibitor,or ANA-12,a TrkB inhibitor.ICSⅡ also decreased both protein level and activity of PDE5.Notably,ICSⅡ might effectively bind and inhibite PDE5 as demonstrated by relatively high binding score.CONCLUSION ICSⅡ significantly protect against cerebral ischemia/reperfusion injury in rats and rescues OGD/Rinduced hippocamp
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Acta Mechanica Sinica Acta Geologica Sinica Acta Metallurgica Sinica Acta Geologica Sinica Acta Mechanica Solida Sinica Acta Oceanologica Sinica Acta Pharmacologica Sinica Applied Mathematics and Mechanics The Journal of China Universities of Posts and Telecommunications Applied Mathematics:A Journal of Chinese Universities 东北大学学报·社会科学版 浙江大学学报·理学版