| Objective: To investigate the anti-dementia effects and its mechanism of2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione?DMDD?on the learning and memory ability,inflammatory factor,neurotransmitter,free radical,apoptosis factor of APP / PS1 transgenic dementia model mice.Methods: The APP / PS1 transgenic dementia model mice were randomly divided into following groups: model control group,huperzine A group(0.03mg·kg-1·d-1),high dose of DMDD group(50 mg·kg-1·d-1),medium dose of DMDD group(25 mg·kg-1·d-1),low dose of DMDD group(12.5 mg·kg-1·d-1),10 mice per group.The mice were intragastrically administered with drugs for 21 days.Meanwhile,10 APP/PS1 normal mice were considered as normal control group and were given equal volume of saline.Morris water maze test was used to observe the changes of learning and learning ability of mice;the morphological changes of hippocampal tissue were also observed;the activities and contents of cholinergic neurotransmitters,inflammatory factors,free radicals and monoamine neurotransmitters of mice brain tissues weredetected.The levels of apoptosis factors,?-amyloid precursor protein??-APP?,?-amyloid protein?A??and Tau protein phosphorylation in hippocampus of dementia mice were detected by immunohistochemistry method.Western blot was used to determine the expressions of Bax and Bcl-2 in brain tissues.Results:?1?DMDD could reduce the escape latency of the APP / PS1 transgenic dementia model mice in hidden platform test experiment,reverse test experiment and visual platform test experiment,and also increase the frequency of crossing the original platform;?2?HE results showed that hippocampal pyramidal cells were ischemic changes and degeneration in DMDD groups,but the number of degeneration and loss of cells were less than the model group.In the DMDD group,the neurons in the DMDD group were normal,the nucleus was slightly depressed,the nucleolus was obvious,there are numerous mitochondria,rough endoplasmic reticulum and the number of free ribosomes.The endoplasmic reticulum was expansible,lysosomes and lipofuscin particles were more than those in the model group.Moreover,there are many protrusions in the nerve felt and synaptic structures,but cavitation structures,neural lines and mitochondria disappear were observed.?3?The activity of ChAT and ACh content were enhanced by DMDD,however,the activity of AChE and levels of inflammatory factor TNF-?,IL-6,IL-1? and IL-8 were reduced.Meanwhile,the contents of DA,NE and 5-HT in brain tissues were increased.?4?DMDD could increase the activities of SOD and GSH-Px in brain,reduce the MDA,NO levels and NOS activity.?5?DMDD could decrease the expressions of Pro-apoptotic factors p53,Bax in dementia mice hippocampus,and increase the expression of inhibitory factor Bcl-2 and the contents of APP and A?,as well as the positive cells of Tau?pSer202?phosphorylated,inhibit the apoptosis of hippocampal neurons.Conclusion:DMDD could reduce the ACh degradation,inhibit the formation of inflammatory factors,regulate the synthesis of monoamine neurotransmitters,inhibit hippocampal neuronal apoptosis and reduce Tau protein phosphorylation.Based on this,we could speculate that DMDD may exert anti-dementia effect through inhibiting the formation of APP and A?,reducing A? protein aggregation and precipitation,which inhibit the Tau protein abnormal phosphorylation,reducing the damage of A? and Tau protein abnormal phosphorylation on hippocampal neurons,improving the hippocampal neurons of the organizational structure,reducing the level of inflammatory factors and improving antioxidant capacity.Finally,gradually restore the normal cholinergic neurotransmitter and monoamine neurotransmitter generation and metabolism,inhibit the occurrence of apoptosis. |
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