Effects of Yishen Jiannao Formula on neuronal apoptosis in vascular dementia rats based on Nrf2/NQO1/GCL pathway
Objective To investigate the effects and mechanism of action of Yishen Jiannao Formula(YSJNF)on neuronal apoptosis in rats with vascular dementia(VD).Methods Sixty SPF-grade rats were randomized into a model preparation group(n=50)and a blank group(n=10).The model preparation group underwent staged ligation of the bilateral common carotid arteries,while the blank group had only separation of the bilateral common carotid arteries without ligation.Four weeks after surgery,28 rats with successful model preparation,as confirmed by the Morris water maze test,were randomized into model group,donepezil group(0.45 mg·kg·d-1),as well as high-dose(24.3 g·kg-1·d-1)and low-dose(12.15 g·kg-1·d-1)YSJNF groups,with seven rats in each group,coupled with the blank group(n=10),totaling five groups.Four weeks after administration,Morris water maze was used to assess the learning and memory abilities of the rats.HE staining was employed to observe the histopathological changes in the cerebral cortex and hippocampal CA1 area,and TUNEL staining to evaluate the neuronal apoptosis in these areas.Immunohistochemistry was used to check the protein expression levels of cysteinyl aspartate-specific proteinase-3(Caspase-3)and cysteinyl aspartate-specific proteinase-7(Caspase-7)in the cerebral cortex and hippocampal CA1 area,and Western blot to examine the protein expression levels of nuclear factor-E2-related factor 2(Nrf2),quinone oxidoreductase 1(NQO1),and glutamate-cysteine ligase(GCL)in the hippocampal tissue.Results Compared with the blank group,the model group showed a significantly increased escape latency on the 5th day of the place navigation test,a significantly decreased number of the platform crossings in the spatial probe test,and a significantly shorter time spent in the target quadrant(P＜0.01);it also exhibited significant pathological damage of the brain tissue and a markedly increased neuronal apoptosis rate(P＜0.01);the positive expressions of Caspase-3 and Caspase-7 in the cerebral cortex and hippocampal CA1 area were significantly elevated(P＜0.01),while the protein expressions of Nrf2,NQO1,and GCL in the hippocampal tissue were notably reduced in this group(P＜0.01).Compared with the model group,the donepezil group and high-and low-dose YSJNF groups showed a significant reduction in the escape latency on the 5th day of the place navigation test,an increase in the number of platform crossings,and an obviously longer time spent in the target quadrant in the spatial probe test(P＜0.05,P＜0.01);these groups also demonstrated reduced pathological damage in the brain tissue and a significant decrease in neuronal apoptosis rate(P＜0.01);furthermore,the positive expressions of Caspase-3 and Caspase-7 were significantly reduced(P＜0.01),while the protein expressions of Nrf2,NQO1,and GCL in hippocampal tissue were significantly elevated in these groups(P＜0.01).Conclusion YSJNF may improve the learning and memory abilities in VD rats,inhibit the protein expressions of Caspase-3 and Caspase-7,and reduce neuronal apoptosis,the mechanism of which may be related to the activation of the Nrf2/NQO1/GCL signaling pathway.
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