Effect of Ganoderma lucidum triterpenoids on cognitive impairment and BDNF-TrkB-CREB signa-ling pathway in scopolamine model mice
Objective To investigate the effect and mechanism of Ganoderma lucidum triterpenoids(GLTs)on improving scopolamine-induced learning and memory impairment and anxious-and depressive-like behavior mice based on brain-derived neurotrophic factor(BDNF)-tyrosine kinase receptor type B(TrkB)-cAMP response element binding protein(CREB)pathway.Methods Fifty SPF-grade female KM mice aged 3 months were randomly divided into control group,model group,GLTs low-dose group(0.35 g/kg),GLTs medium-dose group(0.70 g/kg)and GLTs high-dose group(1.40 g/kg),with 10 mice in each group.The mice in GLTs low-dose,GLTs medium-dose and GLTs high-dose group were given corresponding GLTs by gavage once a day according grouping for 34 days,while mice in control group and model group were given the same volume of 0.9％NaCl by gavage once a day for 34 days.From 22nd day to 34th day of the experiment,except the mice in the control group,mice in the other groups all received intrap-eritoneal injections of scopolamine(3 mg/kg,once a day)to establish the learning and memory impairment model.The learning and memory ability of mice were assessed by Morris water maze and Y maze tests.The anxious-and depressive-like behavior of mice were assessed by elevated plus maze and forced swimming test.The morphology of neurons in hippocampus and cortex were observed by hematoxylin-eosin(HE)stai-ning.The expression levels of postsynaptic density-95(PSD-95)and synaptophysin(SYN),and proteins re-lated to the BDNF-TrkB-CREB pathway in the hippocampal region were detected by Western blot and ELISA.GraphPad Prism 9.0 software was used for statistical analysis.Repetitive measurement ANOVA was used for the multiple group comparison of Morris water maze data.One-way ANOVA was used for the multiple group comparison of the other data,and Tukey multiple test was used for further pairwise comparison.Re-sults(1)The interaction between the time and group on the escape latencies showed no significant among the 5 groups of mice(F=0.77,P=0.58).However,the main effects of group and time on escape latency were both significant among the 5 groups of mice(F=5.27,41.94,both P＜0.05).From day 3 to day 5,the escape latencies of the medium-dose and high-dose GLTs groups were lower than that of the model group(both P＜0.05).There was a statistically significant difference in the time spent in the target quadrant a-mong the 5 groups in Morris water maze test(F=12.78,P＜0.05),with the medium-dose and high-dose GLTs groups spending more time in the target quadrant than the model group(both P＜0.05).Y maze test results showed that there was a statistically significant difference in the percentage of spontaneous alternation among the 5 groups(F=13.46,P＜0.05).The percentage of spontaneous alternations in GLTs medium-dose group((54.47±2.28)％)and high-dose group((55.39±3.34)％)was significantly higher than that in model group((41.65±4.22)％)(both P＜0.05).(2)The results of the elevated plus maze and forced swimming test indicated that there were statistically significant differences in the time spent in the open arms and the immobility time among the 5 groups of mice(F=25.67,4.40,both P＜0.05).The high-dose GLTs group spent more time in the open arms than the model group(P＜0.05)and had a shorter immobility time than the model group(P＜0.05).(3)The HE staining results showed that there were significant differences in the number of cell necrosis in hippocampal CA3 and cortex in 5 groups(F=12.70,19.55,both P＜0.05).The high-dose GLTs group had a lower number of necrotic cells in both the CA3 region and the corti-cal region compared with the model group(both P＜0.05).(4)The Western blot results indicated that there were statistically significant differences in the protein expression levels of PSD-95,SYN,BDNF,p-CREB and the ratio of p-CREB/CREB in the hippocampal region of the brains of the 5 groups of mice(F=5.62,4.15,5.89,5.62,5.19,all P＜0.05).The ELISA results showed that there were statistically significant differences in the protein expression levels of p-TrkB and the ratio of p-TrkB/TrkB in the hippocampal region of the brains of the 5 groups of mice(F=6.36,10.95,both P＜0.05).The high-dose GLTs group had higher pro-tein expression levels of SYN,PSD-95,BDNF,p-CREB,and a higher ratio of p-CREB/CREB compared to the model group(all P＜0.05).Additionally,the high-dose GLTs group had higher expression levels of p-TrkB and a higher ratio of p-TrkB/TrkB((5.03±1.30)pg/mL,0.56±0.10)compared to the model group((0.88±0.26)pg/mL,0.11±0.03)(both P＜0.05).Conclusion GLTs can improve the learning and memory ability and anxious-and depressive-like behavior in scopolamine model mice,and the mechanism may be related to the up-regulation of BDNF-TrkB-CREB pathway related protein expression and the en-hancement of synaptic plasticity.
Ganoderma lucidum triterpenoidsBDNF-TrkB-CREB pathwayScopolamineAlzheimer's diseaseLearning and memory abilityMice
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