Effects And Mechanisms Of Fisetin On Cognitive Impairment In Lipopolysaccharide-Induced Alzheimer’s Disease Model Rats

Objective:Fisetin is a flavonoid that presented in a number of commonly eaten foods,such as sumac,and has a variety of biological effects,Such neurotrophic,anti-cancer,anti-inflammatory and antioxidant effect,and may have potential effects on neurodegenerative diseases.However,there are few studies on the relationship between Fisetin and learning and memory.Recent studies have shown that Fisetin can facilitate long-term potentiation(LTP)of synaptic transmission and improve memory impairment.This research aims to study the effect and mechanism of Fisetin on cognitive impairment AD rats model induced by LPS.Methods:Male SD rats aged 2-3 months were randomly divided into three groups.The control group and LPS group were given intraperitoneal injection of normal saline and LPS for 7 consecutive days.LPS+Fisetin group was intraperitoneally injected with LPS for 7 days and then intraperitoneally injected with Fisetin for 14 days.The level of Aβ was quantified by a human Aβ42 enzyme-linked immunosorbent assay(ELISA)kits.The open-field test and elevated plus-maze were used to observed the spontaneous activity and anxiety state of experimental rats;the Morris water maze test and fear conditioning test were adopted to detected the memory level of rats.The LTP at the schaffer collateral-CA1 pathways in mouse hippocampal slices were investigated by electrophysiological methods.Expression levels of key proteins of learning and memory in hippocampus were analysed by Western blotting.Results:(1)Elisa results showed that compared with control group,the Aβ deposition was significantly increased in the hippocampal area of rats in the LPS group(p<0.01).And the Aβ deposition in LPS+Fisetin group was significantly reduced compared with LPS group(p<0.01).(2)Open-field test and elevated plus-maze showed that there was no significant difference in spontaneous activity and anxiety state between the three groups(p>0.05).(3)The Morris water maze test showed that in place navigation test,compared with control group,escape latency time in LPS group was significantly extended(P<0.05);compared with LPS group,escape latency time in LPS+Fisetin group was significantly reduced(P<0.05).(4)In the space experiments of the Morris water maze test,compared with control group,the time staying at the platform quadrant and the number of crossing the platform quadrant of LPS group were significantly decreased(p<0.01),the escape latency time significantly increased(p<0.01).Compared with LPS group,the time staying at the platform quadrant and the number of crossing the platform quadrant of LPS+Fisetin group were significantly extended(p<0.05),the escape latency time significantly reduced(p<0.05).(5)In the contextual fear test,the freezing time of the LPS group was reduced significantly compared with control group(p<0.05)and decreased significantly compared with LPS+Fisetin group(p<0.01).(6)In the following fear condidioning test,the freezing time of the LPS group was reduced significantly compared with control group(p<0.05)but the freezing time of the LPS+Fisetin group was extended significantly compared with LPS group(p<0.01).(7)Electrophysiological experiments showed that compared with the control group,LTP was impaired in the hippocampal area of rats in the LPS group(p<0.01).While Fisetin can reverse the LTP of LPS injury(p<0.01).There was no significant difference in PPF between the three groups.(8)The Western blotting results showed that LPS and Fisetin did not affect the total protein expression of CaMKII,ERK1/2 and CREB.However,the phosphorylation level of these proteins was significantly reduced in the LPS group compared with the control group(p<0.01).Compared with the LPS group,the phosphorylation levels of CaMKII,ERK1/2 and CREB in the LPS+Fisetin group were significantly increased(p<0.01 or p<0.05).Conclusion:Intraperitoneal injection of Fisetin significantly reduce the Aβ deposition in the hippocampal area of the LPS-induced AD model rats,improve cognitive function,reverse the LTP damage,and increased the phosphorylation levels of ERK1/2,CaMKII and CREB in hippocampal post-synaptic learning and memory related proteins.Fisetin is a potential drug for the treatment of AD.