Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer disease

OBJECTIVE Alzheimer disease(AD)is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited.Over-activation of N-methyl-D-aspar⁃tate(NMDA)receptors,amyloidβ(Aβ)aggrega⁃tion,a decrease in cerebral blood flow(CBF),and downstream pathological events play impor⁃tant roles in the disease progression of AD.This study seeks to explore the efficacy and mecha⁃nism of action of MN-08,a novel memantine ni⁃trate,in established animal models of AD.METHODS MN-08′s effectiveness as a preventative and therapeutic agent was tested in 2-to 8-month-old APP/PS1 transgenic mice and 9-to 12-month-old 3×Tg-AD mice,respectively.The neuroprotective mechanism of MN-08 was tested in the glutamate cell model.The pharmacokinet⁃ics and safety of MN-08 in vivo were determined in normal rats and beagle dogs.For the behavioral test,Western blotting analysis,pathology,ELISA test and in vitro cell tests,investigators were blinded to the experimental grouping and drug treatment.RESULTS MN-08,a novel meman⁃tine nitrate,was found to inhibit Aβaccumulation,prevent neuronal and dendritic spine loss,and consequently attenuate cognitive deficits in 2-month-old APP/PS1 transgenic mice(for a 6-month preventative course)and in the 8-month-old triple-transgenic(3×Tg-AD)mice(for a 4-month therapeutic course).In vitro,MN-08 could bind to and antagonize NMDA receptors,inhibit the calcium influx,and reverse the dysregula⁃tions of ERK and PI3K/Akt/GSK3βpathway,sub⁃sequently preventing glutamate-induced neuro⁃nal loss.In addition,MN-08 had favorable phar⁃macokinetics,blood-brain barrier penetration,and safety profiles in rats and beagle dogs.CON⁃CLUSION The novel memantine nitrate MN-08 may be a useful therapeutic agent for AD.