Protective Effect And Mechanisms Of Cordycepin Against The A?-Induced Neurotoxicity Injury Model Of AD Via Adenosine A1 Receptor

Alzheimer's disease?AD?is an age-related multifaceted neurodegenerative disorder,it is characterized by the gradual deterioration of cognition and memory in association with a wide range of neuronal deaths.Accumulation evidence highlighted the extracellular deposition of?-amyloid?A??plaques,and intracellular neurofibrillary tangle are associated with the pathogenesis of AD.Although the mechanism underlying the disrupted production and aggregation of A?gives rise to the pathology of AD is yet unclear,A?is known to elevate oxidative stress and calcium dysfunction in the brain of AD patients,as well as,induce apoptotic cell death by initiating the mitochondrial dysfunction.In addition,the increased intracellular calcium concentration can lead to mitochondrial permeability changes and dysfunction,as well as,cell death.Furthermore,downstream of calcium activation,calcineurin is synergistic with A?,resulting in spine loss,synaptic dysfunction,neural network disruption,and cognitive deficits.Cordycepin?3-deoxyadenosine?,an active component of C.militaris,exerts anti-tumor,anti-inflammatory,anti-diabetic,and protective effects on the liver.Previous studies have also implicated that cordycepin affects the central nervous system and exerts neuroprotective effects.Furthermore,accumulating evidence also suggested that cordycepin exerts a protective effect against damage resulting from ischemia/reperfusion insult via abnormal free radical scavenging activity,suppression of neuron hyperactivity.These characteristics indicate that the protective effect of cordycepin may be associated with the antioxidant and anti-excitatory neurotoxicity.Considering the close relation of excitatory neurotoxicity and oxidative stress induced by A?on CNS,cordycepin might be ascribed a neuroprotective effect on the damage induced by A?,preventing the AD-related neurodegenerative diseases.However,the exact neuroprotective effect of cordycepin on CNS damage induced by A?on AD is yet to be elucidated.In this work we aimed to study the protective effect of cordycepin on A?_25-35-induced AD model used by MTT,fluorescent probe,western blotting,whole-cell patch clamp detection technique and molecular biological method.1.The protective effect of cordycepin on the A?_25-35-induced neurotoxicity injury model of AD were studied in cell:The primary neuron induced by A?_25-355-35 as AD model using biochemical experiment.The results showed that cordycepin significantly inhibited A?_25-35-induced cell death,increased cell viability,and reduced ROS production.Ca²⁺-dependent fluorescence and whole-cell current recording showed that abnormal calcium homeostasis induced by A?_25–355–35 is rebalanced by cordycepin.Moreover,cordycepin can also reduce the overactivation of acetylcholinesterase?AChE?,increase in p-Tau expression.2.The protective mechanism of cordycepin on the A?_25-35-induced neurotoxicity injury model of AD were studied in cell:In this part of the experiment,biochemical experiments were used to confirm the neuroprotection of cordycepin is dependent on activation of the adenosine A1 receptor.3.The protective mechanism of cordycepin against the A?_25-35-induced neurotoxicity injury model of AD were studied in brain slice:The experiment explored the effect of cordycepin on hippocampal slices by field excitatory postsynaptic potential?fEPSP?.The results showed that cordycepin can inhibit the abnormally elevated synaptic transmission induced by A?,and the improvement of cordycepin is not blocked by adenosine A1 receptor blocker?DPCPX?.The LTP induced by A?_25-355-35 was depressed singnificantly when comparied to the contral.And the cordycepin could increased the amplitude and lasting tiame of LTP.And the effect of cordycepin could be prevented by the A1AR antagonist?DPCPX?.This result demonstrated that cordycepin had protective effect on AD model induced by A?_25-35,and the related mechanism may be related to reducing oxidative stress level,restoring calcium homeostasis,and improving synaptic plasticity in hippocampus.And the effect of cordycepin can be blocked by adenosine A1 receptor blockers,indicating that cordycepin might exhibit neuroprotective effects on the AD model,via the A1R activation.