Bis(9)-(−)-Meptazinol,a novel dual-binding AChE inhibitor,rescues cognitive deficits and pathological changes in APP/PS1 transgenic mice

Background:Alzheimer’s disease(AD)is a progressive and irreversible neurodegenerative brain disorder,which is the most common form of dementia.Intensive efforts have been made to find effective and safe treatment against AD.Acetylcholinesterase inhibitors(AChEIs)have been widely used for the treatment of mild to moderate AD.In this study,we investigated the effect of Bis(9)-(−)-Meptazinol(B9M),a novel potential dual-binding acetylcholinesterase(AChE)inhibitor,on learning and memory abilities,as well as the underlying mechanism in the APP/PS1 mouse model of AD.Methods:B9M(0.1μg/kg,0.3μg/kg,and 1μg/kg)was administered by subcutaneous injection into eight-month-old APP/PS1 transgenic mice for four weeks.Morris water maze,nest-building and novel object recognition were used to examine learning and memory ability.Aβ levels and Aβplaque were evaluated by ELISA and immunochemistry.Results:Our results showed that chronic treatment with B9M significantly improved the cognitive function of APP/PS1 transgenic mice in the Morris water maze test,nest-building test and novel object recognition test.Moreover,B9M improved cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of the AChE activity,Aβ plaque burden,levels of Aβ and the consequent activation of astrocytes and microglia in the brain of APP/PS1 transgenic mice.Most of important,the most effective dose of B9M in the present study is 1μg/kg,which is one thousand of the dosage of Donepezil acted as the control treatment.Furthermore,B9M reduced Aβ plaque burden better than Donepezil.Conclusion:These results indicate that B9M appears to have potential as an effective AChE inhibitor for the treatment of AD with symptom-relieving and disease-modifying properties.