The Effects Of Butyrylcholinesterase(BChE)inhibitor KP-2 On Fear,Memory And Metabolism In Mice

Butyrylcholinesterase(BChE)was found in plaques preferentially in Alzheimer’s disease(AD)and could be associated with stress disorders.However,BChE was not reported in the studies related to the neurological changes in the early aging and the memory of fear of extinction.This thesis reports studing on fear,memory and metabolism in mice by inhibiting BChE.Animal behavior is widely used to evaluate neurological changes such as learning and memory,spatial memory,episodic fear memory,fear extinction memory,depression and anxiety.In order to understand the effect of the change of BChE enzyme activity on the behavioral state of mice,especially the effect on the memory of fear disappearing,the memory of learning space and the activity ability.We studied 3 to 10 months old homozygous BChE knockout(KO)mice,heterozygous BChE KO mice,and(R)-bambuterol(KP-2)orally administered wild-type(WT)mice,KP-2 nasal administration of WT mice and WT mice in the control group conducted behavioral experiments.KP-2 was a specific and reversible BChE inhibitor,which inhibited the enzyme activity of BChE in mice at a lower dose.The behavioral studies include conditioned fear tests,fear extinction tests,fear arousal tests,Morris water maze tests,open field tests,forced swimming tests,and sugar water preference tests.The results demonstrsted that: 1)BChE KO and KP-2 treatment could significantly enhance the memory of fear condition and accelerate the memory of fear of extinction;2)BChE KO and KP-2 treatment inhibited the recall of fear condition memory in mice;3)BChE KO and KP-2treatment delayed the decline of age-related spatial memory in mice.These results support that BChE inhibition enhances the ability of mice to resist aging-related neurological changes and accelerate the memory of fear extinction memory.This thesis also reported neurological disease risk factor detection and experimental research on metabolic analysis based on desorption electrospray mass spectrometry(DESIMS)in mice.The detection of neurological disease risk factors was completed by ELISA kit and immunohistochemical analysis.DESI-MS image is a high-throughput and non-target method which can be used to visualize the distribution and richness of endogenous and exogenous substances on the tissue slice by in-situ ionization,without the need for chemical labeling or pretreatment of the tissue.Distribution and richness without the need for chemical labeling or pretreatment of the tissue.We conclude: 1)BChE inhibition increased the percentage of Aβ1-42/Aβ1-40 in the serum of mice,and enhanced the ability of the brain to metabolize Aβ toxic protein;2)BChE inhibition reduced the mean optical density of Aβ,GFAP and IBA1 cells in the hippocampus,and reduced the risk of cognitive impairment;3)The increasing of the content of glutamine(Gln)and N-acetyl-L-aspartic acid(NAA)in the brain of BChE KO mice,the brain nerves activity of the mice enhanced.In conclusion,the important finding of this thesis is that inhibiting BChE can accelerate the fear extinction memory,improve episodic memory and increased brain vitality.KP-2 as a BChE inhibitor has potential application valued in the treatment of post-traumatic stress disorder(PTSD)and early cognitive decline.