| Objective:Based on the relation of insulin-signaling transmission and sporadic Alzheimer disease (SAD) and also on the theory of energy metabolism disorder in brain and the theory of tau normal modification, this paper aims at studying the effects of YSW-compound on the ethology of model rats with SAD, ultrastructure of hippocampal neurons, energy metabolism in brain, the activity of enzyme related cholinergic system, phosphorylation of tau protein in brain t issue and glycosylated modification of 0-GlcNAc, and also discussing the possible mechanism of protection and treatment of YSW-compound on SAD. YSW-compound is characterized by ascending yang qi, dispelling pathogenic yin, expelling stagnation, removing phlegm and balancing yin and yang. The dementia model (ICV-SAD) was established by intracerebroventricular injection of streptozotocin (ICV-STZ).Methods:SPF healthy male Sprague-Dawley (SD) rats were divided into six groups randomly:sham-operation group, model group, donepezil control group, YSW low dose, medium dose and high dose groups. The dementia model was established by bilateral intracerebroventricular injection of streptozotocin and their treatment was started on 21st after the second modeling except sham operation group and model group. The treatment groups were given the corresponding drugs respectively through gavage. Meanwhile, model group and sham operation group were given the same volume of distilled water through gavage once per day for two months. After the treatment, the Morris water maze was adopted to test spatial learning and memory ability of the rats. The ultrastructural changes of microtubes in hippocampal CA1 of rats were observed by electron microscope. The energy metabolism of cerebral cortex and the activity of enzyme related mitochondrial function and cholinergic system enzyme were tested by biochemical technique. The immunohistochemistry and western-blot methods were used to test the glycosylated modification levels of tau protein 0-G1 cNAc in brain tissue and the phosphorylated levels in the Thr231 and Ser422 sites, along with the expression changes of OGT and 0-G1 cNAcase enzyme in the process of 0-GlcNAc glycosylated modification.Results:1. Compared with sham operation group, the mean escape latency and total swimming distance of rats with SAD (by ICV-STZ) during place navigation test was longer (P<0.01), but the swimming time of rats with SAD in target quadrant was obviously shorter during space probe test (P<0.01). YSW-compound could significantly shorten the mean escape latency and total swimming distance of rats with SAD during place navigation test, with statistical significance (P<0.05, P<0.01) and could extend the swimming time of rats with SAD in target quadrant during space probe test (P<0.05, P<0.01). Donepezil group, compared with YSW low dose, medium dose and high dose groups respectively, had no significant difference (P>0.05).2. The activity of SDH, COX and Na+-K+-ATPase in cerebral cortex of rats with SAD in model group was lower than sham operation group (P<0.01), while YSW-compound could increase the activity of SDH, COX and Na+-K+-ATPase in cerebral cortex of rats(P<0.05, P<0.01). Donepezil group had no obvious difference in comparison with model group (P>0.05).3. Compared with sham operation group, the activity of ChAT in cerebral cortex of rats with SAD in model group was lower (P<0.01), but the activity of AchE was higher (P<0.01). YSW-compound could increase the activity of ChAT in cerebral cortex of rats and reduce the activity of AchE with statistical significance (P<0.05, P<0.01). Donepezil group, compared with YSW low dose,medium dose and high dose groups respectively, had no significant difference (P>0.05).4. Compared with sham operation group, the glycoproteomics of O-GlcNAc in hippocampal tissue with sWGA enrichment of rats with SAD was lower (P<0.01) and the expression of glycosylated tau protein tested by RL2 and CTD110.6 was also lower (P<0.01). However, YSW-compound could obviously improve the glycoproteomics of O-GlcNAc in hippocampal tissue with sWGA enrichment of rats with SAD and the expression of glycosylated tau protein tested by RL2 and CTD110.6, with statistical significance (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).5. Compared with sham operation group, the expression of OGT in hippocampal tissue of rats with SAD was obviously lower (P<0.01) but the expression of O-GlcNAcase was remarkably higher (P<0.01). However, YSW-compound could significantly improve the expression of OGT in hippocampal tissue of rats with SAD and reduce the expression of O-GlcNAcase, with statistical meaning (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).6. Compared with sham operation group, the expression of phosphorylated P-Thr231 and P-Ser422 of tau protein in hippocampal tissue in the Thr231 and Ser422 sites in model group was significantly higher (P<0.01), while YSW-compound could remarkably reduce the expression of P-Thr231 and P-Ser422 of hippocampal tissue of rats with SAD (P<0.05, P<0.01). Donepezil group had no significant difference from the model group (rats with SAD) (P>0.05).Conclusion:1. The ICV-STZ model rats with SAD is characterized by disorders with the energy metabolism of cerebral cortex, mitochondrial function and cholinergic system, along with the impairment of learning and memory and the abnormal phosphorylat ion of tau protein in the key sites of brain tissue. Moreover, the model has good repeatability, stability and reliability, and also is very appropriate to be used to do basic research and drug screening on rats with SAD.2. YSW-compound could significantly improve the learning and memory ability of rats with SAD and the function of neuron mitochondria in cerebral cortex of rats with SAD, and also adjust the balance between the glycosylated mod if icat ion of tau protein 0-G1 cNAc and the phosphorylat ion in hippocampal tissue. YSW-compound could inhibit the hyperphosphorylation of tau protein in the key sites and the toxicity of tau, and protect the structure and function of microtubes as well as prevent axons from injury...
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