| Alzheimer's disease is a chronic neurodegenerative disease characterized by cognitive dysfunction and impairment of learning and memory.Although the pathological mechanism of AD is still controversial,it is an indisputable fact that a large number of A? appearing in the brain,inducing a series of neurotoxicity have been widely recognized.While oxidative stress and inflammation play important role in neurotoxicity induced by A?,therefore,the research on anti-inflammation and anti-oxidation of AD have become a hot spot.Most of the previous clinical trials on ?-secretase(?-site APP cleaving enzyme,BACE)inhibitors,?-secretase inhibitors,active and passive immunotherapy targeting A ? and inhibition of A ? aggregation ended in failure.Clinical trials mainly focus on mild cognitive impairment(mild cognitive impairment,MCI)and dementia,and it is speculated that the treatment time is too late.Because it is difficult in this stage to control the damage of synapse and mitochondria,oxidative stress and inflammation,and nerve loss caused by abnormal deposition of A?.Some researchers calculated that it has been a long time for A? deposition before the onset of clinical symptoms.A? deposition was estimated to take 19.2 years from the threshold of(11)C-Pi B positivity to the levels observed in AD,12.0 years from the levels observed in healthy controls with low A? deposition to the threshold of(11)C-Pi B positivity.It was estimated to take 4.2 years for hippocampal atrophy and 3.3 years for memory impairment before the onset of dementia,therefore,suggest a prolonged preclinical phase of AD.This provide sufficient time for early and long-term intervention to delay the progression of AD.In 2018,the FDA of America issued a new guide on AD,which will support very early intervention in AD.The clinical progression of AD is divided into three stages: clinical prodromal stage,MCI stage and dementia stage.In 2020,"Lancet Neurol" put forward the concept of subjective cognitive impairment(subjective cognitive decline,SCD),The SCD will be given attention.Some scholars have pointed out that the pathogenesis of AD is caused by the deposition of A?,which leads to many pathophysiological mechanisms,such as oxidative stress,inflammatory reaction,neuron apoptosis and so on.The failure of clinical trials on anti-A? drugs might be related to the action of a single target besides the late treatment.Some scholars have suggested that drugs with multi-target effects should be studied,and very early intervention is the key to the prevention of neurodegenerative diseases such as AD.Therefore,polyphenolic flavonoids with antioxidant and anti-inflammatory effects have received more and more attention.Some studies have found that corn whisker flavonoids have a strong scavenging effect on hydroxyl radical and superoxide anion free radicals,and total flavonoids of Cinnamomum camphora can reduce lymphocyte proliferation and effectively reduce the levels of TNF-? and IL-6 in arthritis rats.Hesperetin is a kind of di-hydroflavonoids extracted from the fruits of Rutaceae plants.In this study,APPswe/PS1dE9 double transgenic mice were used as AD model mice.Hesperetin was used for early intervention for 6 months from the age of 3 months.The aim is to observe the effect of hesperetin early intervention on the intra-cerebral neuron,learning and memory ability of rice,to observe the effect of hesperetin on anti-inflammation and anti-oxidation in mice,so as to provide a theoretical basis for the early intervention of hesperetin and other flavonoids in the occurrence and development of AD,the prevention and treatment of AD.Objective:To explore the effects of hesperitin early intervention on learning and memory ability,neuronal loss,anti-inflammatory and anti-oxygen mechanism in APPswe/PS1dE9 double transgenic mice.Methods:APPswe/PS1dE9 double transgenic male mice(12)were used as model and wild type C57BL/6J male mice as control.Three Hesperetin doses including low(20mg/kg),medium(40mg/kg)and high(80mg/kg)were given intragastric administration once a day for 6 months at the age of 3 months of APPswe/PS1dE9 double transgenic male mice.Morris water maze was used to detect the learning and memory ability of mice in each group.HE staining was used to observe the morphology of neurons in hippocampal CA1 region,The contents of MDA,SOD and GSH were detected.Western Blotting was used to detect the protein expression levels of TLR2,NF-? B and HO-1 in brain tissue.Results:1.Effect of early intervention of hesperidin on the learning and memory ability of mice: compared with the control group,the latency of the model minimum in the Morris water maze space exploration test was significantly prolonged(P < 0.05);Compared with the model group,the escape latency was significantly shortened on the 5th day in the low,middle and high dose groups(P < 0.05).In the platform withdrawal experiment,the number of mice crossing the platform in the model group was significantly less than that in the control group(P < 0.05),and the times of crossing the platform in the three dose groups were significantly higher than those in the model group(P < 0.05).2.Effect of hesperetin early intervention on neurons in hippocampal CA1 region of mice: in the control group,the arrangement of neurons in hippocampal CA1 region was regular,and the cell morphology and structure was basically normal.Compared with the control group,the number of neurons in the hippocampal CA1 region of the model group was reduced and disordered,with typical cell damage such as cytoplasmic condensation,nuclear pyknosis,marginalization and blurred nucleoli.Compared with the model group,after the intervention of hesperidin,the number of neurons in the CA1 area of the hippocampus increased,arranged more regularly,and the morphology was significantly improved.3.Effect of early intervention of hesperetin on the contents of MDA,SOD and GSH in brain tissue of mice: compared with the blank group(5.83±1.12)nmol/mg,the level of MDA in the brain tissue of model group(8.31 ± 0.95)nmol/mg mice increased significantly(P <0.05);Compared with the model group,the low,middle and high dose groups of hesperidin can decrease the level of MDA in brain tissue(P<0.05).Compared with the blank group(98.44±4.27)U/mg,the level of SOD in the brain tissue of model group(78.7±12.25)U/mg mice decreased significantly(P<0.05);Compared with model group,the level of SOD in the brain tissue increased in the low,middle and high dose hesperidin groups.Compared with the blank group(13.82 ±2.95)U/mg,the level of GSH in the brain tissue of model group(5.18±1.1)U/mg mice decreased significantly(P<0.05);Compared with model group,the level of GSH in the brain tissue increased in the low,middle and high dose hesperidin groups(P<0.05).4.The effect of hesperidin early intervention on the expression of TLR2,NF-? B and HO-1 protein in the brain tissue of mice:Compared with the control group,the level of TLR2 in the brain tissue of the model group increased significantly(P < 0.05).Compared with the model group,the level of TLR2 in LD,MD and HD hesperetin groups decreased significantly(P < 0.01).Compared with the control group,the level of NF-? B in the brain tissue of the model group was significantly increased,and the level of NF-? B in the LD,MD and HD hesperetin groups were lower than that in the model group.Compared with the control group,the level of HO-1 of brain tissue in the model group showed an upward trend,compared with the model group,the level of HO-1 of the brain tissue in the LD,MD groups increased significantly,while the HO-1 in HD group decreased(LD,HD groups P < 0.01,MD group P < 0.05).Conclusion:The early intervention of hesperidin can protect the brain neurons of APPswe/PS1dE9 double transgenic mice and improve the learning and memory ability of mice.The possible mechanism may reduce the content of MDA,TLR2 and NF-? B in the brain tissue of double transgenic mice and increase the production of SOD,GSH and HO-1. |
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