Phosphodiesterase 5 Inhibitor Yonkenafil Protects Against Learning And Memory Impairment In Experimental Models Of Alzheimer's Disease

Alzheimer's disease(AD)is neurodegenerative disorder clinically characterized by processive cognitive function decline,which expresses senile plaques(SP)and neurofibrillary tangles(NFT)as pathophysiological hallmarks in the brain,is accompanied by degeneration of synapses and death of neurons.Many findings have shown that the phosphodiesterase 5(PDE5)inhibitors such as sildenafil,vardenafil and tadalafil are also active for cognitive enhancement.Yonkenafil is a new type of PDE5 inhibitor in our country.In our previous study,yonkenafil exerts its anti-inflammatory effect in lipopolysaccharides(LPS)-activated N9 microglial cells and it may be partly acted through the NF-?B/NADPH/ROS pathway and concern with cyclic guanosine monophosphate(cGMP)and cyclic adenosine monophosphate(cAMP)pathway.Furthermore,yonkenafil inhibits microglial activation by decreasing PDE5 expression and increasing the cGMP level,downregulates extracellular signal-regulated kinases 1 and 2(ERK1/2)/the NF-?B pathway.In vivo test,we find yonkenafil can increase the number of survival neurons in ischemic brain via the cGMP/Nogo-R pathway.Furthermore,yonkenafil could protect the structure and function of synapses by increasing the levels of BDNF/TrkB and NGF/TrkA.But the effect of yonkenafil on AD that has not been reported.Accordingly,in the present study,we first used the scopolamine model to confirm the neuroprotection of yonkenafil in mice.Then we adopted intracerebroventricular(i.c.v.)streptozotocin(STZ)model and APP/PS1 transgenic model and combined neuroethology,immunohistochemistry and immunoblotting to investigate the neuroprotective effect of yonkenafil and clarify the mechanism,and to offer some references and inspirations for the clinical studies.The study found that:1.Yonkenafil was administrated to scopolamine-treated mice by i.p.at 10 mg/kg for 14 days.The results showed yonkenafil significantly attenuated scopolamine induced learing and memory deficits in mice.2.Yonkenafil was administrated to STZ-treated rats by i.p.at 3 and 10 mg/kg for 21 days,the cognitive damage of icv-STZ rats was significantly improved and the neuronal death was attenuated.In addition,Yonkenafil reduced the number of activated microglia and astrocytes,and downregulated the levels of proinflammatory markers in the prefrontal cortex and hippocampus via decreasing PDE5 protein expression.Furthermore,yonkenafil(3 mg/kg)significantly prevented changes in tau hyperphosphorylation via inhibiting JNK and GSK3? activation induced by STZ.In summary,our study suggested that yonkenafil had strong neuroprotective effect in STZ induced sporadic Alzheimer's disease rats.3.Yonkenafil was administrated to APP/PS1 transgenic mice by i.p.at 6 and 18 mg/kg for 3 months.The results showed that yonkenafil improved nesting-building ability,ameliorated working memory deficits in the Y-maze task,and significantly improved learning and memory function in the MWM task.In addition,yonkenafil reduced the area of A? plaques,and inhibited over-activation of microglia and astrocytes in prefrontal cortex and dentate granule(DG)region of hippocampus.Furthermore,yonkenafil increased the number of newborn neuron in the DG region of APP/PS1 mice.These results suggested that yonkenafil could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing,inhibited the over-activation of microglia and astrocytes as well as restored the number of newborn neuron.In summary,this study suggested for the first time that yonkenafil exerted their therapeutic effects on AD models and improved the learning and memory deficits in these models.In addition,this paper find that the mechanism is that yonkenafil can increase the number of survival neurons in brain via regulating the PDE5 protein expression,inhibiting the neuroinflammation,reducing A? depostion and tau hyperphosphorylation levels,increasing the number of newborn neuron in DG as well as ameliorating the JNK and GSK3? activation in hippocampus.This study will provide important experimental basis for developing yonkenafil for treating AD drugs.