Effects Of Fisetin On Cognitive Impairment In Schizophrenia Model Rats And Its Mechanism

Objective:Schizophrenia(SZ)is a mental illness that seriously impairs the cognitive function of patients.This study used MK-801 induced schizophrenia model mice,using Chinese medicine extract Fisetin to intervene in SZ model mice,to investigate whether fisetin reverses MK-801-induced cognitive impairment in SZ model mice and explores its mechanism of action.Methods:SD(Sprague Dawley)rats at 6 days of birth were randomly divided into control group(Control group),SZ model group(SZ group)and lutein group(Fisetin group).At day7,the SZ group and the Fisetin group were intraperitoneally injected with MK-801 for 7 consecutive days,and the Control group was intraperitoneally injected with the same volume of normal saline for 7 consecutive days.At day60,the fisetin was injected intraperitoneally for 2 weeks in the Fisetin group,and the same volume of dimethylsulfoxide(DMSO)was injected in the Control group and the SZ group for2 weeks.The elevated plus-maze and open field test were used to detect the anxiety and spontaneous activity of rats.The Morris water maze test and the fear conditioning test were used to evaluate the learning and memory abilities of rats.The correlation between hippocampus and learning and memory abilities of rats was analyzed by Western blotting experiments Protein expression;explore the long-term potentiation of the schaffer collateral-CA1 region in rat hippocampal slices using electrophysiological methods.Results:1.Behavioral experiment results suggest that there is no significant difference in anxiety and spontaneous activity levels between the three groups of SD rats in the elevated plus-maze experiment and the open field experiment(P> 0.05).During the training experiment of Morris water maze,the escape latency was significantlyprolonged in SZ group compared with Control group(P<0.05),and significantly decreased in Fisetin group compared with SZ group(P<0.05).In the space exploration test of the Morris water maze,compared with the controlz group,the rats in the SZ group significantly reduced the movement time in the quadrant of the target platform,the number of times they reached the original position of the target platform was also significantly reduced,and the escape latency time was also significantly increased(P <0.01);Compared with the SZ group,the rats in the Fisetin group significantly increased the movement time in the quadrant of the target platform,the number of times they reached the original position of the target platform increased significantly,and the escape latency time also decreased significantly(P <0.05 or0.01).In the experimental stage of the fear conditioning test,compared with the rats in the Control group,the percentage of dead time in the SZ group was significantly reduced(P <0.01).Compared with the rats in the SZ group,In the Fisetin group,the percentage of stagnation time was significantly increased(P <0.01).In the sound experiment stage of the fear conditioned test,compared with the controlz group,the percentage of stagnation time in the SZ group was significantly lower(P <0.01).Compared with rats in the SZ group,the percentage of stagnation time of the rats in the Fisetin group increased significantly(P <0.01).2.The results of immunoblot experiments showed that there were no significant differences in the expression levels of ERK1/2,CREB and CaMKII in the three groups of rats(P> 0.05).Compared with the control group,the SZ group rats had ERK1/2,CREB,CaMKII phosphate The level of phosphorylation was significantly reduced(P <0.05 or 0.01);compared with the rats in the Fisetin group,the phosphorylation levels of ERK1/2,CREB,CaMKII increased significantly(p <0.01).3.Field electrophysiological results suggest that there is no significant difference between the three groups(paired-pulse facilitation,PPF);compared with the rats in control group,the rats in the SZ group,its LTP in the hippocampal CA1 region is impaired(P <0.01),and fisetin can reverse the LTP damage induced by MK-801 in hippocampal CA1 region of SZ model rats(P <0.01 Fisetin group vs.SZ group).Conclusion:Analysis of comprehensive behavioral,molecular biology,electrophysiology and other experimental results shows that continuous intraperitoneal injection of fisetin can increase the phosphorylation of post-synaptic and memory-related proteins ERK1/2,CREB,CaMKII in hippocampus of SZ model mice induced by MK-801 Levels and reversions to LTP injury in the hippocampal CA1 region,thereby playing a role in improving synaptic plasticity and cognitive impairment.Fisetin may be a potential and promising drug for schizophrenia.